QSAR analysis of some phthalimide analogues based inhibitors of HIV-1 integrase

Ruchi Bansal,Piyush Trivedi,C Karthikeyan,N S Hari Narayana Moorthy

doi:10.3998/ark.5550190.0008.f08

Abstract

A quantitative structure activity relationship (QSAR) study has been performed on phthalimide analogues based inhibitors of HIV-1 integrase to understand the structural features influencing the affinity of these inhibitors towards the enzyme. The compounds in the selected series were characterized by molecular descriptors calculated using the QSAR software Dragon and molecular modeling software ChemOffice 2001. QSAR models were derived by stepwise multiple regression analysis employing the method of least squares. The best QSAR model describing the HIV-1 integrase inhibitory activity of phthalimide analogues was selected on the basis of statistical significance and predictive ability as gauged by cross-validation procedure and external test-set method. The generated QSAR models revealed that increased HIV-1 inhibitory potency of tricyclic phthalimide derivatives could be achieved by increasing the overall lipophilicity of the molecules and by incorporating halogen substituents in the benzylic aromatic ring attached to the phthalimido nitrogen atom. Additionally, the model also suggests that the increase in the molecular flexibility by incorporation of rotatable bonds is conducive for HIV-1 inhibitory activity of phthalimide derivatives whereas increase in molecular branching appears to be detrimental to the activity.

Highlights

The alarming spread of the acquired immuno-deficiency syndrome (AIDS) epidemic has stimulated the discovery of therapeutic agents to inhibit the replication of the causative virus, human immunodeficiency virus (HIV).[1]
A Quantitative Structure-Activity Relationship (QSAR) study is performed on these series in order to analyze the physicochemical and structural requirements of these inhibitors to exhibit optimal inhibitory potency of HIV-1 integrase enzyme which will in turn help in rationalizing the design of these molecules as integrase inhibitors
The positive coefficient of the descriptor in model 2 suggests that increase in the overall lipophilicity of the molecule will in turn increase the HIV-1 integrase inhibitory activity of phthalimide derivatives

Summary

Introduction

The alarming spread of the acquired immuno-deficiency syndrome (AIDS) epidemic has stimulated the discovery of therapeutic agents to inhibit the replication of the causative virus, human immunodeficiency virus (HIV).[1]. The derived QSAR models were used for the prediction of the activity values of the compounds in the test set and the external validation parameter, predictive r2 (r2pred) was calculated for evaluating the predictive capacity of the model.

Results

Conclusion