Pharmacophore modeling, atom based 3D-QSAR and Molecular docking approaches to screen C-X-C chemokine receptor type 4 antagonists as microbicides for human immunodeficiency virus-1.

The C-X-C chemokine receptor type 4 receptor CXCR4 which acts as a co-receptor for human immunodeficiency virus-1, expressed in the later stages of infection is considered as an attractive and new target for drug design. Microbicides acting as co-receptor blockers are highly significant as these drugs block HIV lifecycle at early stage itself. The urgent need for a safe and effective microbicide urges to explore new CXCR4 antagonists which could be developed as microbicides. The pharmacophore based 3D-QSAR models and docking models were developed using PHASE and GLIDE modules of Schrodinger software. Three-dimensional quantitative structure-activity relationships (3D-QSAR) studies and pharmacophore modelling was carried out on a dataset of 114 CXCR4 antagonists with the intention of exploring entry inhibitors with better therapeutic potential. A training set of 43 compounds was used to create 3D-QSAR models and they were validated using a test set of 28 compounds. CXCR4 antagonists with good inhibitory activity could be designed and structurally modified based upon the QSAR model developed with necessary pharmacophore features. The results revealed that the common pharmacophore hypothesis ADHPR.1 was used for 3D-QSAR model development and the most active compound, CXCR4 antagonist no.44 which is a imidazopyridine-tetrahydro-8-quinolinamine derivative interacted with the CXCR4 receptor residue ASP 97 by the formation of a hydrogen bond. Also, the docking studies were carried out for the dataset for analyzing the binding conformation of CXCR4 and 114 antagonists. The results obtained from the 3D-QSAR studies and docking simulation can be used for designing new and potent CXCR4 antagonists. The compound identified from this study can be taken up further for validation by in vitro/in vivo studies.