Abiraterone and D4, 3-keto Abiraterone binding to CYP17A1, a structural comparison study by molecular dynamic simulation.

• Conserved H-bond of Asn_202 and 3b-OH groups stabilizes Abiratreone orientation. • D4,3-keto Abiraterone accepts H-bond from Arg-239, so show different H-bond pattern. • Van der Waals interactions dominate both heterocyclic inhibitors binding to CYP17A1. • Water molecules play crucial roles as competitors/accelerators in the H-bond network. The importance of computer-aided drug design and development is clear nowadays. These approaches smooth the way of designing some efficient candidates based on drugs in use. At this place, we studied the mechanism of D4-abiraterone (D4A), the active metabolite of Abiraterone (Abi), binding to CYP17A1 compared with Abi. The molecular dynamics simulation results reveal that the metabolite, which lacks the key 3β-OH group, has a varied H-bond forming pattern. The critical H-bond between 3β-OH of Abi with Asn_202 turns to 3 Keto-O of D4A with Arg_239 in the substrate-binding site. This interaction causes a remarkable distance of 0.63 nm between D4A nitrogen and Fe in heme, which reduces its 17,20 lyase selectivity. The D4A keto moiety presents an immense number of H-bond with surrounding solvent molecules compared with the Abi hydroxyl group. As a result, D4A develops a weaker H-bond network with the enzyme. Otherwise, the heterocyclic nature of inhibitors helps for noticeable van der Waals interaction formation with CYP17A1. However, Abi stabilized position in the binding site helps more van der Waals interactions deposition than D4A. These results convinced the importance of the conserved H-bond for acquiring the proper position by the substrate or inhibitor in the binding site. [ABSTRACT FROM AUTHOR]