Exploring the potency of currently used drugs against HIV-1 protease of subtype D variant by using multiscale simulations

• Published in: Journal of biomolecular structure & dynamics 2021-02, Vol.39 (3), p.988-1003
• Main Authors: Sk, Md Fulbabu, Roy, Rajarshi, Kar, Parimal
• Format: Article
• Language: English
• Subjects: dynamic cross-correlation (DCC); HIV-1/subtype D protease; homology modeling; molecular dynamics; molecular-mechanics Poisson-Boltzmann surface area (MM-PBSA)
• ISSN: 0739-1102; 1538-0254
• DOI: 10.1080/07391102.2020.1724196

Acquired immune deficiency syndrome (AIDS) is caused by the human immunodeficiency virus (HIV), type 1 and 2. Further, the diversity in HIV-1 has given rise to many serotypes and recombinant strains. The currently used protease inhibitors have been developed for subtype B, although non-B subtype strains account for ∼ 90% of the global HIV infections. Subtype D is spreading rapidly and infecting a large population in North Africa and the Middle East. In the current study, molecular dynamics simulations in conjunction with the molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) scheme was used to investigate the potency of four drugs, namely atazanavir (ATV), darunavir (DRV), lopinavir (LPV) and tipranavir (TPV) against the subtype D variant. Our calculations predicted that the potency of the inhibitors decreased in the order TPV > ATV > DRV > LPV. TPV was found to be the most potent against subtype D due to an increase in van der Waals and electrostatic interactions and reduction in the desolvation energy compared to other inhibitors. This result is further supported by the hydrogen bond interactions between inhibitors and protease. Furthermore, our analyses suggested that the binding of TPV induced a more closed conformation of the flap compared to apo or other complexes. It was observed that TPV/PR D has a lower cavity volume relative to the other three complexes leading to a tighter binding. The open conformation of the flap was observed for LPV/PR D . We expect that this study might be useful for designing more potent inhibitors against HIV-1 subtype D. Communicated by Ramaswamy H. Sarma