Molecular insight into the interaction mechanisms of an annulated pyrazole (DB08446) with HIV-1 RT: a QM and QM/QM′ study

Quantum mechanical and hybrid QM/QM′ ONIOM methodology have been applied to investigate the structure and molecular interactions between DB08446 and the binding site of HIV-1 RT. The binding energy calculated using the ONIOM2(M06-2X-D3/6-311 + G(2df,2p):PM6) method is − 369.43 kJ/mol, demonstrating that DB08446 can strongly bind to HIV-1 RT. The pairwise interaction energy analysis at the M06-2X-D3/6-311 + G(2df,2p) and RI-PWPB95-D3/def2-QZVPP levels of theory disclose that there are more attractive interactions than repulsive interactions in the binding site. In particular, residues Lys103, Val106, Tyr188, and Trp229 were major contributors for DB08446 binding to HIV-1 RT. Further detailed structure analysis and NCI visualization confirm that the H-bond, X-bond, π–π, CH•••π, and van der Waals interactions, etc. were the dominant stabilization factors of non-bonded interaction between DB08446 and the binding site of HIV-1 RT.