Computer-Aided Molecular Design of CCR2 - CCR5 Dual Antagonists for the Treatment of NASH

Non-alcoholic fatty liver disease (NAFLD), one of the most common liver diseases, is caused by the disruption of hepatic lipid homeostasis by various metabolic disorders. The progression of NAFLD into Non-alcoholic steatohepatitis (NASH) is mediated by inflammatory chemokines, cytokines, mitochondrial dysfunction, and oxidative stress resulting in hepatocyte inflammation, ballooning, apoptosis, and activation of hepatic stellate cells (HSC). NASH can further lead to cirrhosis, hepatic carcinoma, and also it is predicted to be a major cause of liver transplantation over the next 10 years. Chemokine receptors are majorly involved in recruiting the monocytes in the liver where they are converted into pro-inflammatory macrophages, which further activate the hepatic stellate cell (HSCs) to promote their survival while activating collagen production and fibrogenesis. Thus, chemokines and their receptor play a vital role in the pathogenesis of NASH and can be a potential target for the treatment of NASH. Herein, in this study, we have carried out a structure-based design of CCR2 and CCR5 dual antagonists. We performed pharmacophore mapping studies followed by virtual screening of commercial database to obtain novel molecules which can potentially act as CCR2 and CCR5 dual antagonists. We also performed molecular docking studies of newly obtained hits molecules to see their interactions with both CCR2 and CCR5 receptors. Non-alcoholic By evaluating the chemical structures of the top five molecules, it was observed that all five molecules possess C2 symmetry. The docking results of the top five molecules showed that Thr284, Trp86, Tyr89, and Glu283 (in CCR5) and Asp283, Val37, Asn286, His202, and Gln288 (in CCR2) residues were involved in hydrogen bond interactions. The molecules also showed π-π stacking interaction with key residues Phe112, Tyr108, Phe109, Trp86, and Tyr89 (in CCR5) and HIE121, Trp98, Tyr120 (in CCR2). Additionally, in some molecule’s halogen bond was also observed. The residues which formed the halogen bond include Phe182, Thr195 (in CCR5), and Lys38 (in CCR2). The screened molecules showed the interactions with some key residues i.e., Phe112, Tyr108, Phe109 (in CCR5) and Trp98, Tyr120 (in CCR2) as same that of CVC interactions with CCR5 and CCR2 receptor.