Abstract
Cytochrome P450 (CYP) monooxygenases are versatile drug-metabolizing enzymes that primarily catalyze the metabolism of drugs, steroids, and carcinogens. CYP comprises a vast subfamily of heme-thiolate proteins engaged in the oxidative metabolism of exogenous and endogenous compounds. CYP2S1 is a dioxin-inducible member of CYP, and its expression has been found in tumors of epithelial origins, including colorectal cancer. The absence of structural information regarding targets has hampered drug design. The present study focuses on generating the 3D structure of the target protein using computational tools and exploring its structural features to identify binding sites, mutational changes, and hydrogen-bonding patterns, thereby facilitating the rational design of drugs. The predicted CYP2S1 model, with a quality factor of 88.9, was subsequently bound to the heme cofactor to support the transport, catalysis, and metabolism of CYP2S1. The heme iron binds to the Cys-440 residue of CYP2S1 at a distance of 2.176 \AA , as observed in NMR 3D structures of the CYP family. Ligand-based pharmacophore modeling is employed to identify novel molecules that target CYP2S1. Drugs and inhibitor-based pharmacophore screening identified four novel compounds, namely ZINC8724186 (–10.0 kcal/mol), ZINC71405941 (–9.1 kcal/mol), ZINC48265078 (–8.7 kcal/mol), and ZINC10342365 (–8.0 kcal/mol), that exhibited higher binding affinity for CYP2S1. Docking analysis revealed that residues F117, Y298, A302, T306, I371, and C440 are crucial for receptor-ligand interactions and effective therapeutics. The screened molecules also have better ADMET properties than drugs and reported inhibitors. It has been concluded that ZINC8724186 is a promising natural compound with better pharmacokinetic properties for effective drug repurposing. The novel findings, based on an in-silico approach, may be significant for the design of potent drugs against colorectal cancer and CYP2S1.