HIV-1 protease is a key enzyme for viral maturation because it cleaves precursor
polypeptides into mature structural and functional proteins. The introduction of protease inhibitors into
therapy in the mid-1990s has dramatically changed the AIDS panorama worldwide. However,
resistance to currently available protease inhibitors remains a serious challenge that must be overcome.
Herein, we report a fragment-based QSAR study of a series of highly potent HIV-1 protease inhibitors,
as well as the structural basis of their binding affinity. Hologram QSAR (HQSAR) analyses were
performed, resulting in robust statistical models that consistently correlated the bioactivity profile with the twodimensional
molecular descriptors. The robustness of the best model was assessed based on the correlation coefficients (q2
= 0.70 and r2 = 0.90), as well as the prediction of the activity of an external test set (r2
pred = 0.75). Structure-based
molecular modeling studies were performed to investigate the binding mode of the best inhibitor in the active site of the
enzyme. The HQSAR model and the structural findings provide valuable insights for the rational design of structurally
related HIV-1 protease inhibitors.
Keywords: AIDS, HIV, HQSAR, hologram, inhibitors, molecular modeling, docking, protease.
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