Pharmacophore Identification and QSAR Studies on Substituted Benzoxazinone as Anti-Platelet Agents: kNN-MFA Approach

Prafulla B Choudhari

doi:10.3797/scipharm.1112-09

Abstract

The three-dimensional quantitative structure–activity relationship (3D-QSAR) and pharmacophore identification studies on 28 substituted benzoxazinone derivatives as antiplatelet agents have been carried out. Multiple linear regression (MLR) method was applied for QSAR model development considering training and test set approaches with various feature selection methods. Stepwise (SW), simulated annealing (SA) and genetic algorithm (GA) were applied to derive QSAR models which were further validated for statistical significance and predictive ability by internal and external validation. The results of pharmacophore identification studies showed that hydrogen bond accepters, aromatic and hydrophobic, are the important features for antiplatelet activity. The selected best 3D kNN-MFA model A has a training set of 23 molecules and test set of 5 molecules with validation (q2) and cross validation (pred_r2) values 0.9739 and 0.8217, respectively. Additionally, the selected best 3D QSAR (MLR) model B has a training set of 23 molecules and test set of 5 molecules with validation (r2) and cross validation (pred_r2) values of 0.9435 and 0.7663, respectively, and four descriptors at the grid points S_123, E_407, E_311 and H_605. The information rendered by 3D-QSAR models may lead to a better understanding and designing of novel potent antiplatelet molecules.

Highlights

Cardiovascular and other vascular diseases like cerebrovascular diseases attract much attention in the realm of medical and drug research due to their threat as a main cause of morbidity and mortality
The field values of compounds in the cluster of most active compounds decide the range of field values which is preferred and recommended for new compound design
The structural requirement of the benzoxazinone analogs to show anti-platelet activity is elaborated by the Multiple linear regression (MLR) studies

Summary

Introduction

Cardiovascular and other vascular diseases like cerebrovascular diseases attract much attention in the realm of medical and drug research due to their threat as a main cause of morbidity and mortality. Platelets play a major role in hemostasis and in arterial thrombosis. QSAR approach [1,2,3,4,5,6,7,8,9,10] is certainly useful for drug design for both known and unknown targets. The improvement in three-dimensional structural information (3D) of bioorganic molecules with fast alignment has led to the development of 3D descriptors which are associated with 3D-QSAR methods. QSAR approaches that employ 3D descriptors have been developed to address the problems of 2D-QSAR techniques, such as their inability to distinguish stereoisomers. The present article is an attempt to develop QSAR models based on three-dimensional quantitative structure–activity relationship (3D-QSAR) methods for benzoxazinone compounds

Methods

Results

Conclusion