Revealing drug interactions: A computational study of non-P450 metabolizing enzymes

Abstract

Despite comprehensive studies on P450 enzymes, studies on non-P450 enzymes are rather limited and the mechanism by which the non-P450 enzymes participate in the drug metabolism is not fully understood. Thus, we aimed to analyze the interactions between ester-containing FDA-approved drugs and three non-P450 drug-metabolizing enzymes (Bche, Bphl, and Ces1), and to investigate the structural features of their active sites using computational methods. The interaction between 920 FDA approved drugs that contain a carbonyl group (ester), and three esterase enzymes, Bche, Bphl, and Ces1 were assessed by means of computational methods. Data show that Bche and Ces1 accommodates more drugs than Bphl with 478 and 341 drugs that have docking score/molecular weight ratio greater than 0.15 respectively. In addition, there are distinct structural differences between drug binding sites of three enzymes. Ces1 has multiple solvent channels that reach the binding cavity while Bche does not have any distinct solvent channel. The volume of substrate binding site of Bche's is 1256.75 & Aring;(3) which is the greatest among others. MD simulations show that Gln-119, Asp-70, and Pro-285 contribute most to the drug binding in Bche enzyme. In addition, His-255, Ser-122, and Asp-155 residues in Bphl and Phe-80, Leu-367 and Asp-286 residues in Ces1 are important for drug binding. Molecular dynamic simulation and docking analyses revealed that ligand binding is driven by both electrostatic hotspots and hydrophobic packing, with stronger ligands like Venetoclax and Revefencin engaging more persistent hydrogen bonds and hydrophobic contacts, highlighting key residues for structure-based drug design. This study provides new insights into the structural and functional features of non-P450 enzymes, offering potential implication for drug metabolism.