Molecular docking, dynamic molecular simulation and in silico ADMET screening study of novel bidentate tetrazolyl-adipate anti-HIV drugs candidate

Abstract

In order to develop specific inhibitors of CYP3A4, we chose new derivatives of adipic acid the 2,5-(5-aryl tetrazol-2yl) dimethyl adipate L₁-L₅. During this study, the Ritonavir molecule known as inhibitor of the cytochrome CYP3A4 are chosen as a reference. A molecular docking simulation on the enzyme 7UAZ is conducted for the ligands L₁-L₅, in order to study the predictive binding affinity and the interaction mechanism of the 5-aryltetrazolyl substituents introduced at positions 2 and 5 of adipic acid. A molecular docking study revealed that the relative activation energy level ranged from –10.1 to –7.6 kcal/mol, falling within the range of Ritonavir at –9.0 kcal/mol, which confirms the stability of the ligands within the studied enzyme. The results show that the binding mode of the ligands on the enzyme 7UAZ varies significantly depending on the substituent at the -C5 position of the tetrazole, with the best results obtained for the ligands L₂ and L₅. Then a comparative study based on silico ADMET properties selected only L₂ as a potential inhibitor of CYP3A4. A 100 ns molecular dynamics simulation on the ligand-protein complex highlights the stability of ligand L₂ within the 7UAZ protein.