Indian Journal of Chemistry

Sect. A: Inorganic, Bio-inorganic, Physical, Theoretical & Analytical

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VOLUME 45A

NUMBER 1

January 2006

CONTENTS

Papers

 

13

 

Molecular Electrostatic Potential (MESP)
studies on the anti-hyperglycemic agents —
2,5-dihydroxyquinones

 

 

 

 

 

 

D S Patel, P Daga, P V Bharatam, R K Dongare & S R Gadre*

 

 

 

 

The mapping of molecular electrostatic potential has been carried out on 2,5-dihydroxyquinone derivatives to identify the common set of electronic characteristics of molecules that act as effective insulin mimetic agents. A force-field based systematic conformational search has also been carried out on each system to obtain the least energy conformer. The coplanarity of the two terminal rings attached to the central 2,5-dihydroxyquinone ring as well as the availability of the nearby oxygen lone pair is seen to play an important role in defining the anti-diabetic activity of the molecules.

 

 

21

 

Sanjeevini: A comprehensive active site directed lead design software

 

 

 

 

B Jayaram*, N Latha, Tarun Jain,
Pankaj Sharma, A Gandhimathi &
Vidhu S Pandey

 

 

 

 

Sanjeevini – a comprehensive active site directed lead compound design software is described. The computational pathway integrates several protocols proceeding from the design of chemical templates to lead-like molecules, given the three dimensional structure of the target protein and a definition of its active site. Issues related to geometry of the molecules, partial atomic charges, docking of candidates in the active site, flexibility and solvent effects are also discussed.

 

 

34

 

QSAR studies on cis-hexa and tetrahydro-phthalazinones : A new class of selective PDE-4 inhibitors

 

 

 

 

 

 

 

 

 

M Lakshmi, Anshuman Dixit & Anil K Saxena*

 

 

 

 

QSAR studies on cis-hexa and tetrahydrophthalazinones suggest that molar refractivity, dielectric energy and some indicator variables best describe the variation in PDE-4 inhibitory activity, both in the training and test set of molecules.

45

 

Effect of electrostatic potential of transition state on the stereoselectivity in ene cyclisation: A theoretical study

 

 

 

 

Sukhendu Roy, Kuheli Chakrabarty,
Nityagopal Mondal  & Gourab Kanti Das*

 

 

 

 

Investigation on the transition structure of the ene reaction between propyne and formaldehyde reveals that negative electrostatic potential is generated around the carbonyl oxygen and acetylenic group. The generated electrostatic potential controls the orientation of the oxygenated substituent present on the forming cyclohexane ring in ene cyclisation. Data on mono substituted transition structures have been used to rationalize the stereoselectivity of an ene cyclisation with polyoxygenated substituents.

 

 

51

 

The pH-controlled antiarrhythmic action of dihydropyridines

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Anamika Awasthi & Arpita Yadav*

 

 

 

 

Ab initio Hartree Fock molecular orbital calculations on Ca2+ channel blockers are reported. The protonated form of the drug is expected to be anchored to the nearest site on the channel and the unprotonated form is capable of obstructing the Ca2+ flow by holding the ion.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

58

 

Non-planar amino groups: Protein structure database analysis and ab initio quantum chemical studies on model systems

 

 

 

 

 

 

 

Dhananjay Bhattacharyya*, Kakali Sen & Shayantani Mukherjee

 

 

 

 

Amino groups of nucleotides or amino acid residues act as important hydrogen bond donors in interactions in bio-molecular stability and recognition. Amino group containing model systems, which donate one of their lone pair electrons from nitrogen atoms during photo-induced electron transfer processes, have been studied by ab initio quantum chemical methods. The amino group of the excited state complex, geometry optimized by
MCSCF/6-31G** basis set, is found to have twisted planar geometry and its pyramidal nature is completely lost.

 

 

68

 

Understanding the structural requirements of triarylethane analogues towards PDE-IV inhibitors: A molecular modeling study

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

P Srivani, K Kiran & G Narahari Sastry*

 

 

 

 

A three-dimensional quantitative structure activity relationship study and a complementary molecular docking analysis have been performed on a series of triarylethanes to determine the structural requirements for phosphodiesterase-IV enzyme inhibition.

 

 

 

77

 

Carbohydrate-based drug design: Recognition fingerprints and their use in lead identification

 

 

 

 

 

 

 

J Rajan Prabu, Vetriselvi Rangannan & Nagasuma Chandra*

 

 

 

 

A structural bioinformatics study of several carbohydrate binding proteins to identify common minimum principles required for the recognition of mannose, glucose and galactose is reported. The study identifies an aspartic
acid – O4 sugar hydroxyl interaction to be highly conserved, which appears to be crucial for recognition of all three sugars. Other interactions are specific to particular sugars, leading to individual fingerprints. These fingerprints have then been used in the identification of lead compounds, using fragment-based design approaches.

 

 

93

 

QSAR study on some synthesized and biologically evaluated glutamine analogs as possible anticancer agents

 

 

 

 

Bikash Debnath, Shovanlal Gayen,
Soma Samanta, Anindya Basu, Balaram Ghosh & Tarun Jha*

 

 

 

 

A QSAR study has been performed using tumor weight inhibition as the parameter for biological activity to identify the chemical structural features required and/or responsible for antitumor activity of 51 different
5- N - substituted - 2 - N - (substituted benzenesulphonyl) glutamines. Results show that the steric and the field effects are important for the anticancer activity of these types of glutamine analogs. At least one free hydrogen atom in the amide moiety is required which plays an essential role for the biological activity.

 

 

100

 

Model chemistry of hydrazides. II. Electronic structure of five-membered aromatic hydrazides

 

 

 

 

 

 

 

 

 

V Ananta Ramam, V V Panakala Rao,
K Rama Krishna & R Sambasiva Rao*

 

 

 

 

The model chemistry of five-membered aromatic hydrazides at SEMO level of theory employing AM1, PM3, SAM1 and MNDO Hamiltonians has been studied using AMPAC 6.7 package. The effect of hetero atom (O, S or N) in cyclopentadiene and the position (2- or 3-) of hydrazide fragment on quantum chemical parameters are reported in the gaseous phase. The stability based on total energy follows the order: furoic > thiophene > pyrrole hydrazides.  The study gives complimentary information in understanding the apparently contradictory physico-chemical properties and biological response of the hydrazides.

 

 

106

 

Variations in binding conformations of small molecules to proteins: A study using Protein Data Bank

 

 

 

 

 

Vijay Kumar, Amit Sharma &
K V Radha Kishan*

 

 

 

 

There are several databases incorporating vast data available on the protein structures and small molecules which are useful for understanding the chemical and biological significance of the entries in these databases. The biological activity of a molecule is directly related to the way the molecule is bound to its target protein. There are many examples in the Protein Data Bank where small molecules are bound to proteins in different conformations. Some features of ligand conformational flexibility are presented .

 

111

 

Application of quantum chemical descriptors in computational medicinal chemistry and chemoinformatics

 

 

 

R Parthasarathi, M Elango, J Padmanabhan,
V Subramanian *, D R Roy , U Sarkar &
P K Chattaraj
*

 

 

 

 

The success of DFT based global and local quantum chemical descriptors in predicting the chemical reactivity and selectivity profiles of several selected systems are highlighted. The applications of global and local descriptors in the development of QSAR and QSPR have been presented for prediction of physical properties of series of alkanes, biological activity of testosterone and estrogen derivatives and toxicity of polychlorinated biphenyls, polychlorinated dibenzofurans and benzidines.

 

 

 

126

 

Topological QSAR modeling of cytotoxicity data of anti-HIV 5-phenyl-1-phenylamino-imidazole derivatives using GFA, G/PLS, FA and PCRA techniques

 

 

 

 

 

 

 

 

 

 

 

 

Kunal Roy* & J Thomas Leonard

 

 

 

 

Cytotoxicity data of anti-HIV 5-phenyl-1-phenylamino-imidazole derivatives have been subjected to QSAR study using topological and structural descriptors applying techniques like stepwise regression, multiple linear regression with genetic function approximation, genetic partial least squares, multiple linear regression with factor analysis as the preprocessing step  and principal component regression analysis.

 

 

 

138

 

Topology of human methionine S-adenosyl-transferase

 

 

 

 

 

 

 

 

Santosh A Khedkar, Alpeshkumar K Malde & Evans C Coutinho*

 

 

 

 

 

 

 

 

146

 

Monitoring the sequence specific intercalation in nucleic acids by 9-substituted acridine-4-carboxamides

 

 

 

 

 

 

 

 

 

R Parajuli & C Medhi*

 

 

 

 

The anticancer drug, 9-substituted acridine-4-carboxamide, intercalates with sequences in nucleic acids. A few analogues of this drug with substituents at 9-position have been chosen for studying the intercalative abilities with Watson Crick base pairs, AT, TA, GC and CG. Ab-initio HF/6-31G** and B3LYP methods are used for calculating interaction energies of drug-sequence complexes and the sequence specificity of drugs are analysed from the interaction energies. The computed interaction energies of various drugs with CG and GC sequences are significantly lower than those of others. Hence, these drugs acquire high specificity for GC and CG sequences.

 

159

 

Interaction of water molecules in non-identical protein structures

 

 

 

 

 

 

 

 

J Jayalakshmi, P Mridula & K Sekar *

 

 

 

 

The interaction of the protein atoms with the surrounding water oxygen atoms has been computed for 392 protein chains from 369 protein structures belonging to 90% non-homologous high resolution (<= 1.5 Å) protein structures with a crystallographic R-factor £ 20%. The average percentage of interactions of water oxygen atoms with the polar atoms of the main chain and side chain are 54% and 46% respectively. The interaction of the acidic residues, aspartate and glutamate, with the water oxygen atoms is more when compared to that of the other residues.

 

 

163

 

Target based high throughput screening and lead designing in pharmaceutical drug industry

 

 

 

 

 

 

 

 

 

 

 

 

Indira Ghosh

 

 

 

 

Unraveling of the genome sequence of several species and the understanding of diseases has helped the biologist to identify several proteins and enzyme as drug targets. The medicinal chemist has taken up the challenge of designing several class of compounds which could posses the characteristics of drug-like properties. Some of the techniques adopted by pharmaceutical industry for drug design, like structure based design and generating leads, small molecules designing and QSAR, novel lead generation using pharmacophore, and optimizing leads using combinatorial chemistry and virtual screening are discussed.

 

 

174

 

A comparison of computer aided drug design methods for calculating relative binding affinities of COX-2 inhibitors

 

 

 

 

 

 

 

 

 

 

 

M Amaravani, R Nageswara Reddy, R Mutyala, G V Reddy, P Reddanna* & M Rami Reddy *

 

 

 

 

The free energy perturbation method is compared with molecular mechanics methods to assess the advantages of each in the estimation of relative binding affinities of COX-2 inhibitors. Qualitative predictions of relative binding free energies of COX-2 inhibitors using molecular mechanics methods are discussed and compared with the corresponding free energy perturbation results. The results indicate that the molecular mechanics methods are useful in the qualitative assessment, while the free energy methods are useful in the quantitative assessment of relative binding affinities of enzyme inhibitors.

 

 

182

 

Functional correlation of cyclooxygenases–1, 2 and 3 from amino acid sequences and three dimensional model structures

 

 

 

 

 

 

 

 

 

 

M Nagini, G V Reddy, G R Hemalatha,
Lalitha Guruprasad & P Reddanna *

 

 

 

 

The sequences of COX-1, COX-2, COX-3, three isoforms of cyclooxygenase, have been analysed and three dimensional model structures have been built for human COX-1, COX-2 and canine COX-3 to characterize the function of cyclooxygenase isozymes. Sequence analysis reveals that COX-3 shares 90% homology with COX-1 and 60% with COX-2. The major differences in the active sites of COX-1 and COX-2 are that Ile 523 in COX-1 is replaced by Val in COX-2, apart from a few mutations at the mouth of the active site. No such differences in the active sites are seen between COX-1 and COX-3 structures and the amino acid residues that differ between COX-1 and COX-3 lie only on the surface of the protein.

 

188

 

Molecular docking studies on pyridine derivatives of glitazones as PPAR? agonists

 

 

 

 

 

 

 

Prasad V Bharatam* & Smriti Khanna

 

 

 

 

FlexX software has been employed to perform molecular docking analysis on a series of glitazones in the active site of PPAR?. FlexX scores and interaction energies of glitazones (I-VII) have been compared with those of the corresponding pyridine (Ip-VIIp) analogs. The study shows that the binding affinities do not significantly change due to the benzene vs. versus pyridine substitution in the central ring of PPAR?. The experimentally observed differences do not originate from the differences in the binding affinities.

 

 

194

 

Comparative 2D and 3D-QSAR of antifungal griseofulvin analogues

 

 

 

 

 

 

 

 

 

 

 

 

 

Dhanshri C Juvale, Shivajirao S Kadam & Vithal M Kulkarni*

 

 

 

 

A series of griseofulvin analogues has been examined to determine the structural requirements of antifungal activity by 3D-QSAR studies using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods. Evaluation of 22 compounds (training set) has established the CoMFA and CoMSIA models, which have been validated by evaluation of a set of four compounds (test set). Further, a QSAR analysis has been carried out using Tools for Structure-Activity Relationship software. The QSAR models from these methods exhibit considerable correlative and predictive properties. The models obtained from the present study may be useful for the development of new griseofulvin analogues as potential antifungals.

 

 

202

 

A quantitative and a qualitative study of the resonance assisted double proton transfer in formic acid dimer

 

 

 

 

 

 

 

 

 

 

 

Sharan Shetty , Sourav Pal  *, Dilip G Kanhere & Annick Goursot

 

 

 

 

The double proton transfer in formic acid dimer has been investigated by ab initio molecular dynamics. The study shows that the double proton transfer in the formic acid dimer is due to the formation of Speakman-Hadzi type of short strong hydrogen bonds, and resonance assisted hydrogen bond at the transition state.

 

 

 

 

Authors for correspondence are indicated by (*)

 

 

 


Indian Journal of Chemistry

Vol. 45A, January 2006, pp. 13-20

 

Molecular Electrostatic Potential (MESP) studies on the anti-hyperglycemic agents — 2,5-dihydroxyquinones

D S Patel, P Daga, P V Bharatam*, R K Dongare & S R Gadre*

Received 12 December 2004, revised 14 November 2005

The mapping of Molecular Electrostatic Potential (MESP) has been carried out on 2,5-dihydroxyquinone derivatives to bring out the common set of electronic characteristics of molecules that act as effective insulin mimetic agents. A force-field based systematic conformational search has also been carried out on each system to obtain the least energy conformer. The geometry optimization of the lowest energy conformer is carried out using quantum chemical B3LYP/3-21G method on each system to obtain the wave function. The MESP isosurface plots have been generated and the critical point characteristics estimated for these molecules. The coplanarity of the two terminal rings attached to central 2,5-dihydroxyquinone ring as well as the availability of the nearby oxygen lone pair is seen to play important role in defining the anti-diabetic activity of the molecules.

 

Indian Journal of Chemistry

Vol. 45A, January 2006, pp. 21-33

 

Sanjeevini: A comprehensive active site directed lead design software

B Jayaram*, N Latha, Tarun Jain, Pankaj Sharma, A Gandhimathi & Vidhu S Pandey

Received 12 September 2004; revised 4 December 2005

Sanjeevini – a comprehensive active site directed lead compound design software, based on the on-going research in our laboratory, is described here. The computational pathway integrates several protocols proceeding from the design of chemical templates to lead-like molecules, given the three dimensional structure of the target protein and a definition of its active site. A conscious attempt has been made to handle the target biomolecule and the candidate drug molecules at the atomic level retaining system independence while providing access for systematic improvements at the force field level. Concerns related to geometry of the molecules, partial atomic charges, docking of candidates in the active site, flexibility and solvent effects are accounted for at the current state-of-the-art. To ensure theoretical rigor, binding free energy estimates are developed for candidate molecules with the target protein within the framework of statistical mechanics. We present herein, the technical and scientific features of Sanjeevini, its validation and scope for further improvement. Some modules of Sanjeevini have been made accessible at http://www.scfbio-iitd.res.in/drugdes/sanjeevini.html.

 

Indian Journal of Chemistry

Vol. 45A, January 2006, pp. 34-44

 

QSAR studies on cis-hexa and tetra-hydrophthalazinones: A new class of selective PDE-4 inhibitors

M Lakshmi, Anshuman Dixit & Anil K Saxena*

Received 21 January 2005; revised 8 November 2005

Quantitative structure activity relationship studies have been carried out on cis-hexa and tetra-hydrophthalazinones, a new class of selective PDE-4 inhibitors. The 78 compounds analyzed were divided into a training set of 62 and test set of 15 molecules (excluding one compound) each describing a similar range of biological activity. Among several 2D and 3D parameters, the molar refractivity, dielectric energy and structural parameters as indicator variables (I1, I2, I3) best describe the variation in PDE-4 inhibitory activity in the training set with high correlation(r=>0.9) of >99% significance. These equations also show a good test set prediction (r>0.8) and thus may be useful in designing new potential PDE4 inhibitors.

 

Indian Journal of Chemistry

Vol. 45A, January 2006, pp. 45-50

 

Effect of electrostatic potential of transition state on the stereoselectivity in ene cyclisation: A theoretical study

Sukhendu Roy, Kuheli Chakrabarty, Nityagopal Mondal  & Gourab Kanti Das*

Received 16 November 2004; revised 31 October 2005

Investigation on the transition structure of the ene reaction between propyne and formaldehyde reveals that negative electrostatic potential is generated around the carbonyl oxygen and acetylenic group. The generated electrostatic potential controls the orientation of the oxygenated substituent present on the forming cyclohexane ring in ene cyclisation. Data from the study of mono substituted transition structures have been used to rationalize the stereoselectivity of an ene cyclisation with poly oxygenated substituents.

 

Indian Journal of Chemistry

Vol. 45A, January 2006, pp. 51-57

 

The pH-controlled antiarrhythmic action of dihydropyridines

Anamika Awasthi & Arpita Yadav*

Received 13 October 2004; revised 2 December 2005

Investigations on the ab initio Hartree Fock molecular orbital calculations on Ca2+ channel blockers, in conjunction with intermolecular interaction calculations are reported here. The effect of substitution in the phenyl/pyridyl ring on the activity of the compound is discussed. The conformational mapping clearly indicates the differences in the disposition of phenyl ring with respect to the pyridyl ring. These differences lead to significant differences in terms of interactions with the Ca2+ ion and are able to explain the differences in the activity of o-, m-, and p-nifedipine. The Ca2+ ion holding capacity of the drugs has been investigated by drug-ion interaction energy calculations. The results indicate that the unprotonated form of the drug is capable of blocking the channel by holding the ion on the essential side of the drug, while the protonated form is not capable of holding the Ca2+ ion. Depending on the state of protonation/unprotonation, a possible mechanism explaining use dependent blockade by DHP’s has been suggested. The change in pH could result in change in state of protonation and thus on/off interactions with the Ca2+ ion.

 

Indian Journal of Chemistry

Vol. 45A, January 2006, pp. 58-67

 

Non-planar amino groups: Protein structure database analysis and ab initio quantum chemical studies on model systems

Dhananjay Bhattacharyya*, Kakali Sen & Shayantani Mukherjee

Received 13 December 2004; revised 14 November 2005

Hydrogen bond is one of the most important interactions in bio-molecular stability and recognition. Amino groups of nucleotides or amino acid residues act as important hydrogen bond donors in such interactions. The positions of the hydrogen atoms, which determine the directionality of the hydrogen bonds, are generally not available in the PDB entries. Although, such positions are reported in a few crystal structures, analysis of their geometry indicates that in most of them the positions are not thoroughly refined. The pyramidal nature of a few well-refined amino groups, however, indicates that a strong correlation exists between the non-planarity of the amide and the peptide torsion angles. The pyramidal nature of the amino groups might arise due to effect of lone pair electrons at the central nitrogen atoms, which do not take part in extended conjugation. In order to establish the above hypothesis, we have also studied a few amino group containing model systems by ab initio quantum chemical methods, which donate one of their lone pair electrons from nitrogen atoms during photo-induced electron transfer processes. The amino group of the excited state complex, geometry optimized by MCSCF/6-31G** basis set, is found to have twisted planar geometry and the pyramidal nature is completely lost. This further supports the effect of lone-pair electrons in the vicinity of a conjugated system in amino group non-planarity.

 

Indian Journal of Chemistry

Vol. 45A, January 2006, pp. 68-76

 

Understanding the structural requirements of triarylethane analogues towards PDE-IV inhibitors: A molecular modeling study

P Srivani, K Kiran & G Narahari Sastry*

Received 1 November 2004; revised 11 November 2005

A three-dimensional quantitative structure activity relationship study has been performed on a series of 44 triarylethanes to determine the structural requirements for phosphodiesterase-IV (PDE-IV) enzyme inhibition. Considering the stereochemistry of the data set molecules and the varied types of alignments available, a total of seven models are presented. While most models were optimized to yield satisfactory r2 and q2 values, the best model was obtained with 29 molecules including all the R conformation with r2 0.996, q2 0.510 and r2pred 0.744. A complementary molecular docking analysis is carried out considering the 29 stereochemically characterized set of molecules. The CoMFA maps and the docking studies were used to understand the structural requirements for the PDE-IV inhibition. These studies are expected to provide useful insights into the roles of various substitution patterns on the triarylethane skeleton and also help to design more potent compounds.

 

Indian Journal of Chemistry

Vol. 45A, January 2006, pp. 77-92

 

Carbohydrate-based drug design: Recognition fingerprints and their use in lead identification

J Rajan Prabu1, Vetriselvi Rangannan2 and & Nagasuma Chandra2*

Received 3 December 2004; revised 17 November 2005

Abstract

 

 

Carbohydrate-based therapeutics is a rapidly developing theme, resulting directly from the recent increase in interest in the biological roles of carbohydrates. A fundamental requirement for successful drug design is a detailed understanding of protein-carbohydrate interactions. This article reports a structural bioinformatics study of several carbohydrate binding proteins to identify common minimum principles required for the recognition of mannose, glucose and galactose, which indeed form much of the basis for recognition of higher sugars. The study identifies an aspartic acid – O4 sugar hydroxyl interaction to be highly conserved, which appears to be crucial for recognition of all three sugars. Other interactions are specific to particular sugars, leading to individual fingerprints. These fingerprints, have then been used in the identification of lead compounds, using fragment-based design approaches. The results obtained by such guided design protocols are found to be more focused than those obtained from comparable ab-initio design protocols. These studies, apart from providing clues about the usable pharmacophore space for these structures, also prove that the use of fingerprints in a fragment-based ligand design, leads to the design of a sugar-like ligand, mimicking the natural carbohydrate ligand in each of the 8 eight examples studied.

 

Indian Journal of Chemistry

Vol. 45A, January 2006, pp. 93-99

 

QSAR study on some synthesized and biologically evaluated glutamine analogs as possible anticancer agents

Bikash Debnath, Shovanlal Gayen, Soma Samanta, Anindya Basu, Balaram Ghosh & Tarun Jha*

Received 1 December 2004; revised 7 November 2005

An attempt has been made to identify the chemical structural features required and/or responsible for antitumor activity of 51 different 5-N-substituted-2-N-(substituted benzenesulphonyl) glutamines. For this purpose, a QSAR study has been performed using tumor weight inhibition  as the parameter for biological activity. Results show that the steric and the field effects are important for the anticancer activity of these types of glutamine analogs. At least one free hydrogen atom in the amide moiety is required which plays an essential role for the biological activity. The present study will help us in further synthesis of this type of compounds in the future.

 

Indian Journal of Chemistry

Vol. 45A, January 2006, pp. 100-105

 

Model chemistry of hydrazides. II. Electronic structure of five-membered aromatic hydrazides

V Ananta Ramam, V V Panakala Rao, K Rama Krishna & R Sambasiva Rao*

Received 6 October 2004; revised 5 December 2005

The model chemistry of five-membered aromatic hydrazides at SEMO level of theory employing AM1, PM3, SAM1 and MNDO Hamiltonians has been studied using AMPAC 6.7 package. The effect of heteroatom (O, S or N) in cyclopentadiene and the position (2- or 3-) of hydrazide fragment on quantum chemical parameters are reported in the gaseous phase. The stability based on total energy follows the order furoic > thiophene > pyrrole hydrazides.  The heat of formation (HoF) is exothermic for furoic hydrazide only. Pyrrole with hydrazide fragment in the second position has the lowest dipole moment of 1.93 Debye whereas the 3-analogue has 4.9 units. The second order hyperpolarizabilities are smaller, but greater than urea and thiourea. Based on the present values of third order hyperpolarizabilities, the effect of substituents throws light on utility of these compounds with non-linear optical properties. The shapes of these molecules, electrophilic centers and charge distribution are derived from 3D-surfaces and 2D-contours of total electron density (TD), electrostatic potential (ESP) and energies of frontier molecular orbitals (FMOs).  Logarithm of partition coefficient, molecular refractivity and Henry’s constants are also computed. These results offer complementary information in understanding the apparently contradictory physico-chemical properties and biological response of the hydrazides.

Indian Journal of Chemistry

Vol. 45A, January 2006, pp. 106-110

 

Variations in binding conformations of small molecules to proteins: A study using Protein Data Bank

Vijay Kumar, Amit Sharma & K V Radha Kishan*

Received 25 November 2004; revised 23 November 2005

There are several databases incorporating vast data available on the protein structures and small molecules. They are useful in many fields of chemistry and biology for understanding the chemical and biological significance of the entries in the databases. Since the biochemical as well as pharmaceutical sciences are the interface for both chemistry and biology, understanding the effect of chemicals on biological molecules is an important issue. While vast data is being generated on this front, these are not compiled or arranged in a proper way for user-friendly retrieval. The biological activity of a molecule is directly related to the way the molecule is bound to its target protein. There are many examples in the Protein Data Bank where small molecules are bound to proteins in different conformations. Some features of ligand conformational flexibility are presented in this paper.

 

Indian Journal of Chemistry

Vol. 45A, January 2006, pp. 111-125

 

Application of quantum chemical descriptors in computational medicinal chemistry and chemoinformatics

R Parthasarathia, M Elango, J Padmanabhan, V Subramanian*, D R Roy , U Sarkar & P K Chattaraj*

Received 17 November 2004; revised 11 November 2005

During the practice of chemoinformatics, it has been realized that molecular diversity is an essential feature to characterize the reactivity of the molecules. In addition, it is of utmost importance to enrich potential libraries with those molecules which could be converted to suitable drug candidates or omited as toxins. In addition, a paradigm shift in structure-activity relationship has resulted in the integration of various descriptors and quantum chemical descriptors based drug development activities into early stages of lead discovery. In particular, various descriptors are being developed and used to help identify and screen out compounds that are unlikely to become drugs/toxins. This paper highlights the development of recent Density Functional Theory (DFT) based chemical reactivity descriptors and the applications of these descriptors towards the prediction of chemical reactivity, especially in the prediction of toxicity, biological activities and other chemical informatic properties as well as reactive site and group identification and recent developments towards recognition of potentially toxic molecules. Bridging experimental knowledge with effective computational information, management and prediction of various aspects of molecular reactivities thus facilitates the rapid and cost-effective processes and helps focus attention on interesting molecules.

 

Indian Journal of Chemistry

Vol. 45A, January 2006, pp. 126-137

 

Topological QSAR modeling of cytotoxicity data of anti-HIV 5-phenyl-1-phenylamino-imidazole derivatives using GFA, G/PLS, FA and PCRA techniques

 

Kunal Roy* & J Thomas Leonard

Received 25 November 2004; revised 10 November 2005

Cytotoxicity data of anti-HIV 5-phenyl-1-phenylamino-imidazole derivatives have been subjected to QSAR study using topological and structural descriptors applying techniques like stepwise regression, multiple linear regression with genetic function approximation, genetic partial least squares, multiple linear regression with factor analysis as the preprocessing step and principal component regression analysis. Presence of hydrogen bond donor groups appear to be an important feature for reducing the cytotoxicity. Molecular size, shape and branching are also found important for determining the cytotoxicity. Different fragments of the molecules have been identified as significant contributors in modulating the cytotoxicity. Among all parameters used, H_bond_donor and E-state parameters are most prevalent in different models. The quality of equations obtained from the different techniques are in the comparable range (explained variance ranging from 63.9-68.8% while predicted variance ranging from 61.5-64.5%). However, the best equation statistics were obtained with principal component regression analysis (explained variance and predicted variance being 81.0% and 75.8%, respectively).

 

Indian Journal of Chemistry

Vol. 45A, January 2006, pp. 138-145

 

Topology of human methionine S-adenosyltransferase

Santosh A Khedkar, Alpeshkumar K Malde & Evans C Coutinho*

Received 1 November 2004; revised 13 November 2005

Insights into the three-dimensional (3D) structure of the enzyme, Methionine S-adenosyltransferase (MAT), can throw light on its role in humans and help in evolving selectivity attributes of inhibitors targeted at bacterial MAT. We report here a 3D-model of human MAT, using the X-ray structure of MAT from the rat as a template, by comparative protein modeling principles. The resulting model has the correct stereochemistry as gauged from the Ramachandran plot and good 3D-structure compatibility as assessed by the Profiles-3D score. The structurally and functionally important residues (active site) of human MAT have been identified based on information in the rat MAT crystal structure and the point mutation data reported for human MAT. The homology model does conserve the topological and active site features of the MAT family of proteins. However, there exist some differences in the molecular electrostatic potentials (MEP) of MAT from humans and M. tuberculosis. These differences provide a scope for achieving selectivity and specificity of mycobacterium-MAT inhibition over human MAT.

 

Indian Journal of Chemistry

Vol. 45A, January 2006, pp. 146-158

 

Monitoring the sequence specific intercalation in nucleic acids by 9-substituted acridine-4-carboxamides

 

R Parajuli & C Medhi*

Received 1 November 2004; revised 13 November 2005

The anticancer drug, 9-substituted acridine-4-carboxamide, intercalates with sequences in nucleic acids. Some analogues of this drug with substituents at 9-position are chosen for studying the intercalative abilities with Watson Crick base pairs, AT, TA, GC and CG. Ab-initio HF/6-31G** and B3LYP methods are used for calculating interaction energies of drug-sequence complexes and the sequence specificity of drugs are analysed from the interaction energies. The computed interaction energies of various drugs with CG and GC sequences are significantly lower than those of others. Hence, these drugs acquire high specificity for GC and CG sequences. Moreover, stacking interaction of heavy atoms present in sequence and drug stabilizes the optimum structures.

 

Indian Journal of Chemistry

Vol. 45A, January 2006, pp. 159-162

 

Interaction of water molecules in non-identical protein structures

J Jayalakshmi, P Mridula, K Sekar*, S Vaijayanthimala & D Velmurugan

Department of Crystallography and Biophysics, University of Madras, Guindy Campus, Chennai 600 025, India

Received 24 December 2004; revised 2 November 2005

The interaction of the protein atoms with the surrounding water oxygen atoms has been computed for 392 protein chains from 369 protein structures belonging to 90% non-homologous high resolution (<= 1.5 Å) protein structures with a crystallographic R-factor £ 20%. The percentage composition of the polar atoms is found to be 36.3%. An average of 82.55% of water oxygen atoms are found to be in the primary hydration shell and 15.12% in the secondary hydration shell. The average percentage of interactions of water oxygen atoms with the polar atoms of the main chain and side chain are 54% and 46%, respectively. The interaction of the acidic residues, aspartate and glutamate, with the water oxygen atoms is more when compared to that of the other residues.

 

Indian Journal of Chemistry

Vol. 45A, January 2006, pp. 163-173

 

Target based high throughput screening and lead designing in pharmaceutical drug industry

Indira Ghosh

Received 24 February 2005; revised 29 November 2005

Recent advancement in the field of chemoinformatics and computer-aided drug design has aided the pharmaceutical industry to develop more compounds in less time in the pipeline of genome based drug design for specific disease. Unravelling of genome sequence of several species and the understanding of disease has helped the biologist to have several proteins and enzyme as drug targets, which has made the medicinal chemist to take up the challenge of designing of several class of compounds which could possess the characteristics of drug-like properties. Some of the techniques which have made it possible, are discussed here with a preference towards the industry’s approach to the drug designing.

 

Indian Journal of Chemistry

Vol. 45A, January 2006, pp. 174-181

 

A comparison of computer aided drug design methods for calculating relative binding affinities of COX-2 inhibitors

M Amaravani, R Nageswara Reddy, R Mutyala, G V Reddy, P Reddanna* & M Rami Reddy*

Received 31 August 2004; revised 10 November 2005

Computational assessment of the binding affinity of enzyme inhibitors prior to synthesis is an important component of computer-aided drug design paradigms. The free energy perturbation methodology is the most accurate means of estimating relative binding affinities between two inhibitors. However, due to its complexity and computation-intensive nature, practical applications are restricted to analysis of structurally-related inhibitors. Accordingly, there is a need for methods that enable rapid assessment of a large number of structurally-unrelated molecules in a suitably accurate manner. In this article, the free energy perturbation method is compared with molecular mechanics methods to assess the advantages of each in the estimation of relative binding affinities of COX-2 inhibitors. Qualitative predictions of relative binding free energies of COX-2 inhibitors using molecular mechanics methods are discussed and compared with the corresponding free energy perturbation results. The results indicate that the molecular mechanics based methods are useful in the qualitative assessment, while the free energy methods are useful in the quantitative assessment of relative binding affinities of enzyme inhibitors.

 

Indian Journal of Chemistry

Vol. 45A, January 2006, pp. 182-187

 

Functional correlation of cyclooxygenases-1, 2 and 3 from amino acid sequences and three dimensional model structures

M Nagini, G V Reddy, G R Hemalatha, Lalitha Guruprasad & P Reddanna*

Received 30 August 2004; revised 16 November 2005

COX-1, COX-2 and COX-3, three isoforms of cyclooxygenase are differentially expressed. We have analyzed the sequences of these cyclooxygenases and built the three dimensional model structures for human COX-1, COX-2 and canine COX-3 to characterize the function of cyclooxygenase isozymes based on the sequence and structure information. Sequence analysis reveals that COX-3 shares 90% homology with COX-1 and 60% with COX-2. The COX-1 model has been compared with those of COX-2 and COX-3 and the active site regions have been analyzed. The major differences in the active sites of COX-1 and COX-2 are: Ile 523 in COX-1 is replaced by Val in COX-2, apart from a few mutations at the mouth of the active site. No such differences in the active sites are seen between COX-1 and COX-3 structures and the amino acid residues that differ between COX-1 and COX-3 lie only on the surface of the protein. Therefore, it is hard to explain the specificity of acetaminophen towards COX-3. Further, the intron 1 of canine COX-1 gene that is retained in COX-3 mRNA transcript codes for a poly proline region that could be responsible for intermolecular interactions.

 

Indian Journal of Chemistry

Vol. 45A, January 2006, pp. 188-193

 

Molecular docking studies on pyridine derivatives of glitazones as PPAR? agonists

Prasad V Bharatam* & Smriti Khanna

Received 1 November 2004; revised 9 November 2005

FlexX software has been employed to perform molecular docking analysis on a series of glitazones in the active site of PPAR?. FlexX scores and interaction energies of glitazones (I-VII) have been compared with those of the corresponding pyridine (Ip-VIIp) analogs. The results point out that the binding affinities do not significantly change due to the benzene vs. versus pyridine substitution in the central ring of PPAR?. The experimentally observed differences do not originate from the differences in the binding affinities.

 

Indian Journal of Chemistry

Vol. 45A, January 2006, pp. 194-201

 

Comparative 2D and 3D-QSAR of antifungal griseofulvin analogues

 

Dhanshri C Juvale, Shivajirao S Kadam & Vithal M Kulkarni*

Received 21 February 2005; revised 15 November 2005

A series of griseofulvin analogues has been examined to determine the structural requirements of antifungal activity by three-dimensional quantitative structure-activity relationship studies using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods. Evaluation of 22 compounds (training set) has established the CoMFA and CoMSIA models, which have been validated by evaluation of a set of four compounds (test set). The lowest energy conformer of the most active molecule obtained from systematic search has been used as the template structure for the alignment. In this study, the superimposition of molecules was carried out by atom-based fit (rms), multifit and field fit. Along with steric and electronic fields, ClogP has been taken as additional descriptor to account for lipophilicity. Further, a QSAR analysis has been carried out using Tools for Structure-Activity Relationship software. For this study, various chemical descriptors such as electronic, steric, lipophilic, topological have been calculated and multiple regression carried out. The QSAR models from these three methods exhibit considerable correlative and predictive properties. The models obtained from the present study may be useful for the development of new griseofulvin analogues as potential antifungals.

 

Indian Journal of Chemistry

Vol. 45A, January 2006, pp. 202-212

 

A quantitative and a qualitative study of the resonance assisted double proton transfer in formic acid dimer

Sharan Shetty  , Sourav Pal *, Dilip G Kanhere & Annick Goursot

Received 17 November 2004 ; revised 14 November 2005

Ab initio molecular dynamics simulations have been performed to study the nature of the synchronous double proton transfer in formic acid dimer. In order to understand the evolution of the bonding during the double proton transfer, the electron localization function and the molecular orbital isosurfaces have been used. During the dynamics of the double proton transfer in formic acid dimer the two formic acid monomers approach each other, forming Speakman-Hadzi type of short strong hydrogen bonds at the transition state. The Speakman-Hadzi type of short strong hydrogen bonds are also shown to be polar covalent bonds. Based on the concept of resonance assisted hydrogen bond proposed by Gilli et al (Gilli P, Bertolasi V, Ferretti V & G. Gilli, J Am Chem Soc, 116 (1994) 909), it is shown that the proton at the transition state is connected by a p-conjugated O¾C¾O structures, indicating a resonance assisted hydrogen bond. On this basis the double proton transfer process in the formic acid dimer can be termed as a resonance assisted double proton transfer. The present work indicates that the synchronous double proton transfer in the formic acid dimer is due to the formation of (a) Speakman-Hadzi type of short strong hydrogen bonds, and (b) resonance assisted hydrogen bond at the transition state.