In silico study of 1-(4-Phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl) ethanones derivatives as CCR1 antagonist: homology modeling, docking and 3D-QSAR approach

Abstract

C-C chemokine receptor type 1 (CCR1) is a chemokine receptor with seven transmembrane helices and it belongs to the G-Protein Coupled receptor (GPCR) family. It plays an important role in rheumatoid arthritis, organ transplant rejection, Alzheimer's disease and also causes inflammation. Because of its role in disease processes, CCR1 is considered to be an important drug target. In the present study, we have performed three dimensional Quantitative Structure activity relationship (3D-QSAR) studies on a series of 1-(4-Phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl) ethanone derivatives targeting CCR1. Homology modeling of CCR1 was performed based on a template structure (4EA3) which has a high sequence identity and resolution. The highest active molecule was docked into this model. Ligand-based and Receptor-based quantitative structure-activity relationship (QSAR) study was performed and CoMFA models with reasonable statistics was developed for both ligand-based (q(2)=0.606; r(2)=0.968) and receptor-guided (q(2)=0.640; r(2)=0.932) alignment methods. Contour map analyses identified favorable regions for high affinity binding. The docking results highlighted the important active site residues. Tyr113 was found to interact with the ligand through hydrogen bonding. This residue has been considered responsible for anchoring ligands inside the active site. Our results could also be helpful to understand the inhibitory mechanism of 1-(4-Phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl) ethanone derivatives thereby to design more effective ligands in the future.

Keywords: 3D-QSAR; CCR1; Docking; Homology modeling; Receptor-guided CoMFA.