ArticleJournal of molecular modeling2010
Insights into drug resistance of mutations D30N and I50V to HIV-1 protease inhibitor TMC-114: free energy calculation and molecular dynamic simulation.
Article in Journal of molecular modeling, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 38 citations in OpenAlex.
- Investigation of the inhibitory behavior of XFE and mitoxantrone molecules in interaction with AKT1 protein: a molecular dynamics simulation study.Journal of molecular modeling · 2023Article
- Non-active site mutants of HIV-1 protease influence resistance and sensitisation towards protease inhibitors.Retrovirology · 2020Article
- The binding structure and affinity of photodamaged duplex DNA with members of the photolyase/cryptochrome family: A computational study.Biophysics and physicobiology · 2018Article
- Trypsin-Ligand binding affinities calculated using an effective interaction entropy method under polarized force field.Scientific reports · 2017Article
- Exploring the crizotinib resistance mechanism of NSCLC with the L1196M mutation using molecular dynamics simulation.Journal of molecular modeling · 2017Article
- Exploring the drug resistance of V32I and M46L mutant HIV-1 protease to inhibitor TMC114: flap dynamics and binding mechanism.Journal of molecular graphics & modelling · 2015Article
- Article
- A computational analysis of binding modes and conformation changes of MDM2 induced by p53 and inhibitor bindings.Journal of computer-aided molecular design · 2013Article
- Insights into the structural function of the complex of HIV-1 protease with TMC-126: molecular dynamics simulations and free-energy calculations.Journal of molecular modeling · 2012Article
- Interaction of I50V mutant and I50L/A71V double mutant HIV-protease with inhibitor TMC114 (darunavir): molecular dynamics simulation and binding free energy studies.The journal of physical chemistry. B · 2012Article
- Energetic basis for drug resistance of HIV-1 protease mutants against amprenavir.Journal of computer-aided molecular design · 2012Article
- Computational studies of difference in binding modes of peptide and non-peptide inhibitors to MDM2/MDMX based on molecular dynamics simulations.International journal of molecular sciences · 2012Article
- Molecular dynamic simulation insights into the normal state and restoration of p53 function.International journal of molecular sciences · 2012Review
- Molecular dynamics simulation in virus research.Frontiers in microbiology · 2012Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The single mutations D30N and I50V are considered as the key residue mutations of the HIV-1 protease drug resistance to inhibitors in clinical use. In this work, molecular dynamics (MD) simulations combined with the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method have been performed to investigate the drug-resistant mechanisms of D30N and I50V to an inhibitor TMC-114. The analyses of absolute binding free energies using the separate trajectory approach suggests that the decrease in the van der Waals energy and electrostatic energy in the gas phase results in the drug resistance of D30N to TMC-114, while for I50V, the decrease in the electrostatic energy mainly drive its drug resistance to TMC-114. Detailed binding free energies between TMC-114 and individual protein residues are computed by using a per-residue basis decomposition method, which provides insights into the inhibitor-protein binding mechanism and also explains the drug-resistant mechanisms of mutations D30N and I50V to TMC-114. The study shows that the loss of the hydrogen bond between TMC-114 and the side chain of Asn30' is the main driving force of the resistance of D30N to TMC-114, and in the case of I50V, the increase in the polar solvation energies between TMC-114 and two residues Val50' and Asp30' definitively drives the resistance of I50V to TMC-114. We expect that this work can provide some helpful insights into the nature of mutational effect and aid the future design of better inhibitors.
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