Identification of small molecule inhibitors of CXCR4 – an important drug target in renal fibrosis

Abstract

Abstract The final stage of almost all chronic kidney diseases is renal fibrosis (CKD). Following tissue inflammation, the healing process leads to fibrosis. Simple wounds or persistent inflammation can cause tissue inflammation, which, in the case of the kidney, results in scarring. Vascular sclerosis, tubulointerstitial fibrosis, and glomerular fibrosis are all types of kidney fibrosis. Tubular atrophy, tubular dilatation, interstitial leukocyte infiltration, fibroblast accumulation, vascular rarefaction, and persistent matrix protein deposition make up the tubulointerstitial fibrosis histological appearance. Renal damage will therefore be exacerbated and fibrosis will be encouraged by persistently elevated Cxcr4 expression (on tubules or immune cells like macrophages). Since various effector cells, including tubular and infiltrating lymphoid cells, are involved in fibrosis, blocking this pathway should reduce it. This study aimed to identify possible pharmacological agents which could bind to and inhibit isoform I of CXCR4 and determine their strength of interactions. The I-TASSER, Phyre and Robetta were used to predict and refine the structure of the CXCR4 protein. ModBase was used to improve the loops, and then the quality was evaluated using the ERRAT value. The improved 3D structure was subjected to small molecule database docking using Maestro (from Schrodinger) and the glide module. GROMACS was used to simulate molecules with the lowest glide scores and the best ADME properties. For docking studies, we employed the CXCR4 refined structure, which had an ERRAT score of 92.15.%. The maximum glide score was achieved by the ligand 1-[(4-ETHYLPHENYL)METHYL]-4-[(3-NITROPHENYL)METHYL]PIPERAZINE, which was followed by 1-CYCLOHEXYL-4-[(2-NITROPHENYL)METHYL]PIPERAZINE. GROMACS simulation simulations revealed that 1-[(4-ETHYLPHENYL)METHYL]-4-[(3-NITROPHENYL)METHYL]PIPERAZINE and CIITA-I interacted in a more stable manner.