Computational Screening of CCR5 Inhibitors as Potential Entry Inhibitor Microbicides Using 3D-QSAR Studies, Docking and Molecular Dynamics Simulation

Background: The chemokine receptor CCR5 acts as a co-receptor for HIV binding and it is considered as an important target by CCR5 antagonists. Entry inhibitor based microbicides gain much importance nowadays as these drugs act at an early stage of HIV lifecycle and thus hinder the viral replication process in humans. The present study intends to identify a CCR5 antagonist which could be developed as a microbicide using computational approaches. Methods: The pharmacophore modeling and 3D QSAR studies was used to screen CCR5 antagonists with enhanced antagonist activity. The docking studies ranked the compounds according to their bind- ing affinity and molecular dynamics simulation validated the stability of the enzyme-ligand complex. Results: A five point pharmacophore hypothesis HHPRR (2 hydrophobic; 1 positively ionisable; 2 aromatic ring) was generated. A statistically significant 3D QSAR model with 3 PLS factors was gen-erated for common pharmacophore hypothesis HHPRR. 3 with good correlation coefficient value (R-2=0.7483). The docking studies revealed that molecular interaction of CCR5 antagonists having good binding affinity are better than the microbicides taken for this study. The QSAR maps revealed the regions as a combined effect of hydrogen bond donors, hydrogen bond acceptors and hydrophobic groups which denoted the substitution of groups indicating the favorable and unfavorable regions for antagonist activity of hydroxypiperidine derivatives. The docking analysis and molecular dynamics simulation screened and validated CCR5 antagonists. Conclusion: The present study was successful in identifying a CCR5 antagonist which could be developed as a microbicide.