3D QSAR Studies of DAMNI Analogs as Possible Non-nucleoside Reverse Transcriptase Inhibitors

S Ganguly,V Gopalakrishnan

doi:10.1155/2008/712930

Abstract

The non-nucleoside inhibitors ofHIV-1-reverse transcriptase (NNRTIs) are an important class of drugs employed in antiviral therapy. Recently, a novel family ofNNRTIs commonly referred to as 1-[2-diarylmethoxy] ethyl) 2-methyl-5-nitroimidazoles (DAMNI) derivatives have been discovered. The 3D-QSARstudies onDAMNIderivatives asNNRTIs was performed by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods to determine the factors required for the activity of these compounds. The global minimum energy conformer of the template molecule 15, the most active molecule of the series, was obtained by simulated annealing method and used to build the structures of the molecules in the dataset. The combination of steric and electrostatic fields inCoMSIAgave the best results with cross-validated and conventional correlation coefficients of 0.654 and 0.928 respectively. The predictive ability ofCoMFAandCoMSIAwere determined using a test set of tenDAMNIderivatives giving predictive correlation coefficients of 0.92 and 0.98 respectively indicating good predictive power. Further, the robustness of the models was verified by bootstrapping analysis. The information obtained fromCoMFAandCoMSIA3Dcontour maps may be of utility in the design of more potentDAMNIanalogs asNNRTIs in future.

Highlights

The reverse transcriptase (RT) of the Human Immunodeficiency Virus is a key target in the treatment of Acquired Immune Deficiency Syndrome (AIDS) for which no completely successful, chemotherapy is yet available[1].There are two classes of HIV-1-RT inhibitors, the nucleoside (NRTIs) (e.g., AZT, 3TC, ddI, ddC) and the non-nucleosideinhibitors (NNRTIs) depending on their mechanism of action
The Comparative molecular field analysis (CoMFA) model obtained with 30 DAMNI derivatives in training set resulted in a sixcomponent model with cross-validated correlation coefficient of 0.697 and minimum standard error
The 3D-QSAR analyses, CoMFA and Comparative molecular similarity indices analysis (CoMSIA) have been applied to a set of DAMNI analogs active against HIV -1 RT .Statistically significant models with good correlative and predictive power for NNRT inhibitory activities of the DAMNI analogs were obtained

Summary

Introduction

The reverse transcriptase (RT) of the Human Immunodeficiency Virus is a key target in the treatment of Acquired Immune Deficiency Syndrome (AIDS) for which no completely successful, chemotherapy is yet available[1].There are two classes of HIV-1-RT inhibitors, the nucleoside (NRTIs) (e.g., AZT, 3TC, ddI, ddC) and the non-nucleosideinhibitors (NNRTIs) depending on their mechanism of action. 1-[2-(diarylmethoxy)-ethyl] 2-mehyl-5-nitroimidazoles (DAMNIs), a novel family of NNRTIs active at submicromolar concentration has been discovered[8,9,10]. The additional fields in CoMSIA provide better visualization and interpretation of the obtained correlation in terms of field contribution to the activity of the compound. On the basis of CoMFA and CoMSIA models for DAMNI derivatives, we attempted to elucidate a structure/activity relationship to provide useful information for the design and synthesis of more potent DAMNI analogs and related derivatives with predetermined affinities. The total set of DAMNI analogs (40 compounds) was divided into the training set (30 compounds) and test set (10 compounds) (Figure 1).The ratio of training set molecules to test set molecules was in the approximate ratio 4:1.Test and training set compounds were chosen manually such that low, moderate, and high activity compounds were present approximately in equal proportions in both sets.

H Thiophenyl

Results and Discussion

Conclusions