Efficiency of a second-generation HIV-1 protease inhibitor studied by molecular dynamics and absolute binding free energy calculations
Language English Country United States Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
15340915
DOI
10.1002/prot.20192
Knihovny.cz E-resources
- MeSH
- Entropy MeSH
- HIV-1 drug effects enzymology MeSH
- HIV Protease chemistry metabolism MeSH
- Indinavir chemistry pharmacology therapeutic use MeSH
- HIV Protease Inhibitors chemistry pharmacology therapeutic use MeSH
- Protein Conformation MeSH
- Models, Molecular MeSH
- Molecular Structure MeSH
- Drug Design MeSH
- Saquinavir chemistry pharmacology therapeutic use MeSH
- Thermodynamics MeSH
- Protein Binding MeSH
- Hydrogen Bonding MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- HIV Protease MeSH
- Indinavir MeSH
- HIV Protease Inhibitors MeSH
- Saquinavir MeSH
A subnanomolar inhibitor of human immunodeficiency virus type 1 (HIV-1) protease, designated QF34, potently inhibits the wild-type and drug-resistant enzyme. To explain its broad activity, the binding of QF34 to the wild-type HIV-1 protease is investigated by molecular dynamics simulations and compared to the binding of two inhibitors that are used clinically, saquinavir (SQV) and indinavir (IDV). Analysis of the flexibility of protease residues and inhibitor segments in the complex reveals that segments of QF34 were more mobile during the dynamics studies than the segments of SQV and IDV. The dynamics of hydrogen bonding show that QF34 forms a larger number of stable hydrogen bonds than the two inhibitors that are used clinically. Absolute binding free energies were calculated with molecular mechanics-generalized Born surface area (MM-GBSA) methodology using three protocols. The most consistent results were obtained using the single-trajectory approach, due to cancellation of errors and inadequate sampling in the separate-trajectory protocols. For all three inhibitors, energy components in favor of binding include van der Waals and electrostatic terms, whereas polar solvation and entropy terms oppose binding. Decomposition of binding energies reveals that more protease residues contribute significantly to the binding of QF34 than to the binding of SQV and IDV. Moreover, contributions from protease main chains and side chains are balanced in the case of QF34 (52:48 ratio, respectively), whereas side chain contributions prevail in both SQV and IDV (main-chain:side-chain ratios of 41:59 and 45:55, respectively). The presented results help explain the ability of QF34 to inhibit multiple resistant mutants and should be considered in the design of broad-specificity second-generation HIV-1 protease inhibitors.
References provided by Crossref.org
