Amprenavir complexes with HIV-1 protease and its drug-resistant mutants altering hydrophobic clusters

Molecular mechanics analysis of drug-resistant mutants of HIV protease.

Drug-resistant mutants of HIV-1 protease limit the long-term effectiveness of current anti-viral therapy. In order to study drug resistance, the wild-type HIV-1 protease and the mutants R8Q, V32I, M46I, V82A, V82I, V82F, I84V, V32I/I84V and M46I/I84V were modeled with the inhibitors saquinavir and indinavir using the program AMMP. A new screen term was introduced to reproduce more correctly the...

Effects of drug-resistant mutations on the dynamic properties of HIV-1 protease and inhibition by Amprenavir and Darunavir

Molecular dynamics simulations are performed to investigate the dynamic properties of wild-type HIV-1 protease and its two multi-drug-resistant variants (Flap + (L10I/G48V/I54V/V82A) and Act (V82T/I84V)) as well as their binding with APV and DRV inhibitors. The hydrophobic interactions between flap and 80 s (80's) loop residues (mainly I50-I84' and I50'-I84) play an important role in maintainin...

Crystal structures of wild-type and drug-resistant mutants of HIV-1 protease complexed to Ritonavir

Structural implications of drug-resistant mutants of HIV-1 protease: high-resolution crystal structures of the mutant protease/substrate analogue complexes.

Emergence of drug-resistant mutants of HIV-1 protease is an ongoing problem in the fight against AIDS. The mechanisms governing resistance are both complex and varied. We have determined crystal structures of HIV-1 protease mutants, D30N, K45I, N88D, and L90M complexed with peptide inhibitor analogues of CA-p2 and p2-NC cleavage sites in the Gag-pol precursor in order to study the structural me...

HIV-1 protease: mechanism and drug discovery.

It has now been two decades since acquired immunodeficiency syndrome (AIDS) was first reported by the US Center for Diseases Control (CDC). A few years later, it was found that a retrovirus called human immunodeficiency virus (HIV) is the causative agent in AIDS. In a short time, AIDS increased to epidemic proportions throughout the world, affecting more than 40 million people today and killing...