Satya P. Gupta

3D-QSAR studies on quinazoline antifolate thymidylate synthase inhibitors by CoMFA and CoMSIA models.

Thymidylate synthase (TS) is a crucial enzyme for DNA biosynthesis and many nonclassical lipophilic antifolates targeting this enzyme are quite efficient and encouraging as antitumor drugs. Herein, we report some 3D-QSAR analyses using CoMFA and CoMSIA on quinozoline antifolates in order to have a better understanding of the mechanism of action and structure-activity relationship of these compounds. By applying leave-one-out (LOO) cross-validation study, we obtained cross-validated q(2) value of 0.573 for CoMFA and 0.445 for CoMSIA, while the non-cross-validated r(2) values for them were found to be 0.935 and 0.893, respectively. The models were graphically interpreted using CoMFA and CoMSIA contour plots. The results obtained from this study could be used for rational design of potent inhibitors against thymidylate synthase.

Current perspective of HCV NS5B inhibitors: a review.

Hepatitis C virus (HCV) infection has emerged as one of the most significant disease to affect humans. Despite its large medical and economical impact, there are no vaccines or efficient therapies without major side effects. The HCV non-structural protein 5B (NS5B) is the RNA-dependent RNA polymerase responsible for the complete copy of the RNA viral genome and is a target of choice for the development of anti-HCV drugs. Although many small molecules have been identified as allosteric inhibitors of NS5B, very few are active in clinical applications. Developments in the field have prompted us to review the research work on HCV NS5B polymerase inhibitors, especially their structure activity relationships and molecular modeling studies. This review will focus on the journey of drug discovery of HCV NS5B inhibitors covering both nucleoside and non-nucleosides.

A QSAR Study on Some Series of Sodium and Potassium Channel Blockers

A quantitative-structure activity relationship (QSAR) study has been made on two different series of sodium channel blockers--namely, a series of 3-(4-phenoxyphenyl)pyrazoles and a series of 2-alkyl-4-arylimidazoles--and a series of potassium channel blockers that comprises of khellinone derivatives, which act on voltage-gated K(+) channels Kv1.3. In both the cases--the inhibition of Na+ channels or the inhibition of K+ channels--the significant correlations were obtained between the inhibition potencies and the hydrophobic properties of the compounds. This led to suggest that the hydrophobic property of the compounds is a major determining factor of the Na+/K+ channel blocking activity and that the compounds might elicit their effects through the hydrophobic interactions with the receptors.

A Quantitative Structure-Activity Relationship Study on Some Series of Potassium Channel Blockers

There has been an increasing interest in compounds that modulate potassium ion channels (K(+)-channels) since they can be developed as important therapeutic agents against ischemic heart diseases. Of the diverse family of K(+)-channels, the voltage-gated potassium channel Kv1.3 constitutes an attractive target for the selective suppression of effector memory T cells in autoimmune diseases. For the development of antiarrythmic drugs, the blockade of the rapidly activating delayed rectifier (I(Kr)) and slowly activating delayed rectifier (I(Ks)) potassium currents has been specifically studied. Since the discovery of I(Ks)-channel, its blockers have been particularly more studied. In this communication, we present QSAR studies on a few series of Kv1.3-channel blockers and a series of I(Ks)-channel blockers in order to provide some guidelines to the drug development.

Synthesis, in vitro and in silico NS5B polymerase inhibitory activity of benzimidazole derivatives.

Hepatitis C virus (HCV) NS5B polymerase is the key replicating protein of the virus and thus an attractive target for drug development. Here we report on the synthesis and biological evaluation of a new series of benzimidazole derivatives as HCV NS5B inhibitors. This yielded compound 6b and 6d bearing 2-(2-benzyloxy)phenyl and 2-(4-methylbenzyloxy)phenyl moieties, respectively, as promising leads. Binding mode of compound 6d in allosteric pocket (AP)-1 of NS5B will form the basis for future structure-activity relationship optimization.

3D QSAR kNN-MFA studies on thiouracil derivatives as hepatitis C virus inhibitors

The development of new therapies to treat hepatitis C virus (HCV) infection effectively is currently an intensive area of research. To achieve this objective quantitative structure–activity relationship (QSAR) study was carried as it provides the rationale for the changes in the structure to have more potent analogs. In this article, we report 3D QSAR studies for the set of 50 HCV NS5B RNA-dependent RNA polymerase inhibitors using k-Nearest Neighbor Molecular Field Analysis (kNN-MFA) method combined with various selection procedures. By using kNN-MFA approach, various 3D QSAR models were generated to study the effect of steric and electrostatic descriptors on anti-HCV activity. The model with good external and internal predictivity for the training and test set has shown cross validation (q2) and external validation (pred_r2) values of 0.85 and 0.75, respectively. The steric descriptors at the grid points S_430, S_1065, and S_1165 play an important role in the design of new molecule. It also suggests the importance of aromatic or large bulky ring substituent at R1 to increase the HCV inhibitory activity as well as large bulky substituent at R2 reduces activity. This model was found to yield reliable clues for further optimization of thiouracil derivatives in the data set.

A 3D-QSAR Study on a Series of Benzimidazole Derivatives Acting as Hepatitis C Virus Inhibitors: Application of kNN-Molecular Field Analysis

A k nearest neighbor-molecular field analysis (kNN-MFA) of benzimidazole derivatives, a series of hepatitis C virus (HCV) inhibitors, has been performed to determine the factors contributing the corresponding activities. The energy minimized conformations were obtained by molecular mechanics using VLife QSAR 1.0 package. The developed model was verified by performing leave-one out (LOO) cross-validation, which showed q2 value of 0.900 and pred_r2 value of 0.783. The model indicates the dominance of the steric field and also points out the regions around the benzamidazole ring where the bulky or less bulky groups can be substituted to increase the activity of the compounds.

A QSAR study on some series of anti-hepatitis B virus (HBV) agents.

A quantitative structureactivity relationship (QSAR) study has been made on some series of antihepatitis B virus (HBV) agents, namely, a series of novel bis(Lamino acid) ester prodrugs of 9[2(phosphonomethoxy)ethyl]adenine, a similar series of compounds comprising of 2 amino6arylthio9[2(phosphonoethoxy)ethyl] purine bis(2,2,2 trifluoroethyl) esters, and a series of 1isopropylsulfonyl2amine benzimidazoles. In each case significant correlations are found between the antiHBV potencies and some physicochemical and steric properties of the compounds, indicating that for the first two series the activity is controlled by the hydrophobic and the bulk properties of the molecules and, for the third series, the steric and hydrogen bonding properties of compounds are crucial for their antiHBV potency.

A Quantitative Structure–Activity Relationship Study on a Series of Na+, K+-ATPase Inhibitors

A quantitative structure–activity relationship (QSAR) study has been made on a new series of digitalis-like Na+,K+-ATPase inhibitors in which the guanylhydrazone group has been replaced by an aminoalkyloxime group. The correlations obtained have shown that the oxime moiety, primary amine group, overall size, and polarizability of the new type of substituents are higly beneficial to the Na+,K+-ATPase inhibition potency of the compounds and that their effect can be quantitatively assessed. The study also showed that the inotropic activity of the compounds is very well correlated with their Na+,K+-ATPase inhibition potency.

A Quantitative Structure-Activity Relationship and Molecular Modeling Study on a Series of Biaryl Imidazole Derivatives Acting as H

The H+/K+-ATPase or proton pump is a magnesium-dependant enzyme which causes the exchange of a proton against a potassium ion through a membrane. Over activity of this enzyme causes hyperacidity by producing more of hydrochloric acid inside the stomach. This enzyme, therefore, has been found to be a good target for designing compounds to treat hyperacidity. A quantitative structure-activity relationship (QSAR) study has been made on a novel series of biaryl imidazole derivatives acting as H+/K+-ATPase inhibitors. The H+/K+-ATPase inhibition activity of these compounds is found to be significantly correlated with global topological charge indices (GTCIs) and the total polar surface area (TPSA) of the molecules, indicating the involvement of strong electronic interaction between the molecule and the receptor. Based on the correlations obtained, some new H+/K+-ATPase inhibitors are predicted. The docking studies of these predicted compounds exhibit that these compounds will have even better interaction with the receptor than those already marketed. Thus, they can prove more potent drugs for the treatment of hyperacidity.