Insights into the interaction mechanism of first-generation HIV-1 protease inhibitors with wild-type and mutant (D30N and L76V) enzymes through based approach.

The combined effort of medical, scientific and pharmaceutical research has transformed the HIV infection from an inevitably fatal disease into a manageable chronic ailment. Especially after the introduction of protease (PR) inhibitors the efficacy of the treatment regimen has been increased. However, the development of mutant PR enzymes is a major concern. The present study focuses on to understand the alterations in wild-type and mutants (D30N and L76V) PR structure by interaction of first-generation PR inhibitors amprenavir, indinavir, nelfinavir, ritonavir and saquinavir. This information is extracted using molecular docking and MD simulation. Further, post-MD analysis such as RMSD, RMSF, PCA, DCCM, intermolecular interactions and binding free energy values calculation has been done. In comparison to L76V, D30N mutation affected the stable binding of the most of the studied PR inhibitors. The positively charged NH2 and thiazole group of amprenavir and nelfinavir is repelled by NH2 of Asn30 in D30N mutant. This repulsion pushes the drugs towards flap domain and causes flap opening. The MD simulation reveals that amprenavir, nelfinavir and saquinavir drugs have good compatibility with L76V mutant PR enzyme whereas indinavir was affected by the same. L76V mutant does not form any direct interaction with the first line drugs; hence the drugs forming strong interactions with the active site, flap domain and substrate binding region residues are quite enough to manage the resistance provided by L76V mutant. The results provided the insight into the drug-resistant or drug-susceptibility mechanism of L76V and D30N mutation against first-generation PR inhibitors.