Exploration of QSAR modelling techniques and their combination to rationalize the physicochemical characters of nitrophenyl derivatives towards aldose reductase inhibition.

The quantitative structure-activity relationship (QSAR) analysis of nitrophenyls active as aldose reductase inhibitors (ARIs) has been performed employing Fujita-Ban, classical Hansch approach and physicochemical properties. The multivariant regression expressions were developed using sequential multiple linear regression (SEQ-MLR) techniques considering adjustable correlation coefficient (r(2)(adj)). The statistical quality of SEQ-MLR equations were evaluated considering parameters like correlation coefficient (r), standard error of estimation (SEE), and variance ratio (F) at explicit degree of freedom (df). Orthogonality of the descriptors in SEQ-MLR was established through variance inflation factor (VIF).The QSAR analysis gave insight to some common important structural feature i.e. the hydroxyl group is crucial for hydrogen bond interaction with the receptor. Similarly electro-negative substitution is essential for polar interaction with charge region of the receptor. Moreover analysis inferred that diarylsulphides can be explored for optimization of the analogs.

Insights through AM1 calculations into the structural requirement of N-hydroxythiosemicarbazone analogs as anti-tubercular agents.

Fujita-Ban, Hansch substituent constants, topological descriptors and conformational dependent descriptors were explored for quantification of anti-tubercular activity of N-hydroxythiosemicarbazone analogs. All the approaches gave statistically sound model which accounts for more than 88% of the explain variance against anti-tubercular activity except Fujita-Ban (approximately 75%). Fujita-Ban & Hansch approaches having certain limitation, however, another approache showed their significant role in explaining activity of the modified scaffolds. QSAR study of N-Hydroxythiosemicarbazone analogs furnished some important structural insights i.e., the R position is more prone for improving inhibitory activity and the R(1) position play a decisive role in the ionic interaction of the ligand with macromolecules. On the basis of findings, N-hydroxythiosemicarbazones interaction model with macromolecule of M. Tuberculosis has been proposed. These interactions might be helpful in further development of potent anti-tubercular agents.

Exploration of physicochemical properties and molecular modelling studies of 2-sulfonyl-phenyl-3-phenyl-indole analogs as cyclooxygenase-2 inhibitors.

In the present work, modelling study has been performed to explore the physicochemical requirements of 2-sulfonyl-phenyl-3-phenyl-indole analogs as COX-2 enzyme inhibitors. The multivariant regression expressions were developed using sequential multiple linear regression (SEQ-MLR) technique, considering adjustable correlation coefficient (r(adj)(2)). The statistical quality of SEQ-MLR equations was evaluated considering parameters like correlation coefficient (r), standard error of estimation (SEE), and variance ratio (F) at explicit degree of freedom (df). Orthogonality of the descriptors in SEQ-MLR was established through variance inflation factor (VIF). Developed equations have been internally validated using leave-one-out technique and further validated with test set, considering predictive squared correlation coefficient (r(pred)(2)). The orientation of the most potent and selective COX-2 inhibitor of training set, 2-(4-phenyl sulfonamide)-3-phenyl-5-methylindole, in the COX-2 active site was explored by docking. The phenyl sulfonamide moiety positioned in secondary pocket of enzyme which consists of amino acid residues Phe(518), Gln(192), Arg(513), Leu(352), Ser(353) and Val(523) is responsible for the selectivity. The unsubstituted phenyl ring positions in a hydrophobic cavity are lined by Tyr(385), Trp(387), Tyr(348), Leu(384) and Met(522). Interestingly, the indole C-5 CH(3)-substituent is located in a hydrophobic region formed by Ile(345), Val(349), Ala(527), Leu(531) and Leu(534). The hydrophobic interactions of methyl group might be crucial for the potency of 2-sulfonyl-phenyl-3-phenyl-indole analogs. Study has revealed that atomic van der Waals volume and atomic masses explain COX-2 inhibitory activity of 2-sulfonyl-phenyl-3-phenyl-indole analogs significantly.

QSAR studies on benzoylaminobenzoic acid derivatives as inhibitors of beta-ketoacyl-acyl carrier protein synthase III.

Fatty acid biosynthesis is essential for most of the bacterial survival. Components of this biosynthetic pathway have been identified as attractive targets for the development of new antibacterial agents. FabH, beta-ketoacyl-ACP synthase III, is a attractive target since it is central to the initiation of fatty acid biosynthesis. Quantitative structure-activity relationship (QSAR) studies have been carried out on a series of benzoylaminobenzoic acid derivatives as potent inhibitors of FabH and antibacterial activity against Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis, Neisseria meningitidis and Escherichia coli, which demonstrate FabH inhibitory activity in cell free and whole cell system. The QSAR studies revealed that inhibitory activity increases with increase in hydrophobicity, molar refractivity, aromaticity, and presence of OH group (on x position of the nucleus). On the other side presence of hetero-atoms like N, O, or S at R(1) position of the nucleus decreases the inhibitory activity. The comparison of QSAR between the FabH inhibitory activity and antibacterial activity against S. aureus, S. pneumoniae, S. pyogenes, E. faecalis, N. meningitidis also demonstrates that the hydrophobicity, aromaticity and presence of OH group (on x position of the nucleus) are conducive for the inhibitory activity.

Rationalization of physicochemical characters of oxazolyl thiosemicarbazone analogs towards multi-drug resistant tuberculosis: a QSAR approach.

The emergence of multi-drug resistant (MDR) strains of Mycobacterium tuberculosis and the continuing pandemic of tuberculosis emphasizes the urgent need for the development of new and potent anti-tubercular agents. In an effort to develop new and more effective agents to treat tuberculosis emphasis was focused on quantification of structure-activity relationship of oxazolyl thiosemicarbazone derivatives. The de novo analysis gave insight to some important structural features i.e. nitro group on phenyl ring at R(1) position is optimal for the activity and might be responsible for electronic interaction, while phenyl ring at R position interact with the hydrophobic pocket more effectively as compared to unsubstituted or methyl substituted analogs. Hansch approach offered the understanding and parameterization of interactions of the inhibitor with receptor. Similarly QSAR analysis gave some important physicochemical properties, i.e. empirical aromatic index (ARR) and 3D-MoRSE code value of scattering angle at 8A(-1). These two physicochemical properties shall be helpful in the development of more potent analogs.

QSAR analysis of indazole estrogens as selective beta-estrogen receptor ligands: rationalization of physicochemical properties.

Quantification of structure activity relationships was performed on a series of indazole estrogen analogs, for their relative beta estrogenic receptor agonist activity, in order to understand the essential structural requirements for selectivity of indazole estrogen analogs for beta-estrogenic receptor over alpha-estrogenic receptor. The de novo and Hansch approach suggested that the 3(rd) position of indazole nucleus (R(1)) is decisive for the selectivity of molecules towards beta-estrogenic receptor over alpha-estrogenic receptor. The study also depicted that the substitution of polar group at R(1) position might prove helpful in the beta-estrogenic receptor selectivity (ER(beta/alpha )).

Rationalization of physicochemical characters of 1,5-diarylpyrazole analogs as dual (COX-2/LOX-5) inhibitors: a QSAR approach.

Arachidonic acid metabolizing enzymes cyclooxygenases and lipoxygenases lead to the formation of various eicosanoids involved in variety of human diseases, like inflammation, fever, pain, rheumatic and osteoarthritis, etc. Non-steroidal anti-inflammatory drugs are useful tools in the treatment of prostaglandin mediated complications. The development of dual inhibitors may prevent a drift of arachidonic acid metabolism towards the other pathway, leading to potential side effects. Hence emphasis was focused on quantification of structure-activity relationship, with a view to delineating the influence of key COX-2/LOX-5 activity, to explore structural insights to aid the designing of safer dual inhibitors. The quantification of the structural features of 1,5-diarylpyrazole analogs with various biological activities gave some important structural insights, i.e. Hy (hydrophilic factor) and Mor17v (3D molecular representation of structure based on electron diffraction code). These two physicochemical properties may be helpful in development of more selective dual COX-2/LOX-5 inhibitors.

Classical QSAR study on chromene derivatives as lanosterol 14alpha- demethylase inhibitor: a non azole antifungal target.

A lanosterol 14alpha-demethylase inhibitors of chromene series were subjected to classical quantitative structural activity relationship studies. Apart from the indicator variables encoding for different group contribution, there are various physico-chemical descriptors like steric, thermodynamic and electronic parameters, which were applied to explore the structural requirements for inhibition of enzyme. Multiple linear regression analysis shows that substituents on the appended alkylated ether and the carbon chain length, which should not be more than six at R3 and R1 positions in the parent nucleus, are essential to modulate the activity. Electronic parameters such as highest occupied molecular orbital energy and dipole dipole energy have been found to play an important contribution for biological activity. From the orientation or distribution of the total molecular structures in 3D space, it was assessed that Principal Moments of Inertia at X-axis is detrimental for fungal inhibitory activity. Thus validated models bring important structural insights to aid the design of potent lanosterol 14alpha-demethylase inhibitors prior to their synthesis.

Development of pharmacophoric model of condensed pyridine and pyrimidine analogs as hydroxymethyl glutaryl coenzyme A reductase inhibitors.

Quantitative structure-activity relationship (QSAR) has been established on a series of thirty-eight compounds of four different sets of condensed pyridine and pyrimidine analogs, for their hydroxymethyl glutaryl coenzyme (HMG-CoA) reductase inhibitor activity, in order to understand the essential structural requirement for binding with receptor, in terms of common biophoric and secondary sites employing APEX-3D software. Among several 3D pharmacophoric models with different sizes and arrangements, one model was selected based on r2 = 0.8, chance<0.001, match equivalent to 0.38 and all the 38 compounds were considered. The results suggest that hydrophobicity, hydrogen acceptor and optimum steric refractivity play a dominant role in the inhibition of HMG-CoA reductase. The information obtained from the present study can be used to design and predict more potent molecules as HMG-CoA reductase inhibitors, prior to their synthesis.

Quantitative structure-activity analysis of 5-arylidene-2,4-thiazolidinediones as aldose reductase inhibitors.

Design of aldose reductase (ALR2) inhibitors has received considerable attention. Aldose reductase inhibitors, when administered from the onset of hyperglycemia, prevent the progression of polyol accumulation-linked complications. The feasibility that inhibition of aldose reductase provides a pharmacologically direct treatment for diabetic complications that is independent of the control of blood sugar levels has spurred the development of structurally diverse aldose reductase inhibitors. In this work, we report quantitative structure-activity relationship (QSAR) analysis performed by 3D-QSAR analysis, Hansch analysis, and Fujita-Ban analysis on a series of 5-arylidene-2,4-thiazolidinediones as aldose reductase inhibitors. The 2D & 3D-QSAR models were generated using 18 compounds and Fujita-Ban analysis models were obtained using 23 compounds. The predictive ability of the resulting 2D and 3D models was evaluated against a test set of 5 compounds. Analyses of results from the present QSAR study inferred that 3rd position of the phenyl ring and acetic acid substitution at N-position of thiazolidinediones play a key role in the aldose reductase inhibitory activity.

QSAR analysis of thiazole benzenesulfonamide substituted 3-pyridylethanolamines as beta3-adrenergic receptor agonist.

A quantitative structure-activity relationship study on a series of substituted benzene sulfonamide-3-pyridylethanolamines with beta3-adrenergic receptor agonist activity was made using a combination of various physiochemical descriptors. Several significant equations with good co-efficients of correlation (0.930) were obtained; the two models were selected using predictive ability of equations for test set. Both models highlight some common important structural features, that is, high electrostatic potential energy and the lipophilic nature of the molecule, favorable for beta3-adrenergic receptor agonist activity.

Development of 3D-QSAR models for 5-lipoxygenase antagonists: chalcones.

5-Lipoxygenase inhibitors are of current interest for asthma therapy and inflammatory diseases. In order to identify the essential structural and physicochemical requirements in terms of common biophoric sites (pharmacophore) and secondary sites for binding and interacting with 5-lipoxygenase, a series of 51 compounds of chalcones has been used for the development of 3D-QSAR models on APEX-3D expert system. Among several models, the two models have been identified with the statistical criteria R(2)>0.75, Chance <0.001 and Match >0.7. Both the models (nos 1 and 2) with three biophoric sites and four secondary sites, showed very good correlation (r>0.9) between the observed and calculated or predicted activities.