Identifying the Molecular Mechanics and Binding Dynamics Characteristics of Potent Inhibitors to HIV-1 Protease

Dechang Li, Ming S. Liu*, Baohua Ji, Keh Chih Hwang, Yonggang Huang

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Human immunodeficiency virus type 1 protease (HIV-1 PR) is one of the primary inhibition targets for chemotherapy of AIDS because of its critical role in the replication cycle of the HIV. In this work, a combinatory coarse-grained and atomistic simulation method was developed for dissecting molecular mechanisms and binding process of inhibitors to the active site of HIV-1 PR, in which 35 typical inhibitors were trialed. We found that the molecular size and stiffness of the inhibitors and the binding energy between the inhibitors and PR play important roles in regulating the binding process. Comparatively, the smaller and more flexible inhibitors have larger binding energy and higher binding rates; they even bind into PR without opening the flaps. In contrast, the larger and stiffer inhibitors have lower binding energy and lower binding rate, and their binding is subjected to the opening and gating of the PR flaps. Furthermore, the components of binding free energy were quantified and analyzed by their dependence on the molecular size, structures, and hydrogen bond networks of inhibitors. Our results also deduce significant dynamics descriptors for determining the quantitative structure and property relationship in potent drug ligands for HIV-1 PR inhibition. Correlation between the association rate constant and the radius of gyration of inhibitors. The dash black lines is the trend line and the dash red circle highlights the confined region of FDA-approved inhibitors (solid pink-color dots). The inset shows the interaction between the inhibitor and the PR during the binding process.

Original languageEnglish (US)
Pages (from-to)440-454
Number of pages15
JournalChemical Biology and Drug Design
Issue number3
StatePublished - Sep 2012


  • HIV-1 protease
  • Inhibition
  • Ligand binding pathways
  • Molecular dynamics
  • Quantitative structure and property relationship (QSPR)
  • Virtual screening

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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