ArticleJournal of molecular graphics & modelling2015
Exploring the drug resistance of V32I and M46L mutant HIV-1 protease to inhibitor TMC114: flap dynamics and binding mechanism.
Article in Journal of molecular graphics & modelling, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 20 citations in OpenAlex.
- Article
- Benchmarking Machine Learning Models for HIV-1 Protease Inhibitor Resistance Prediction: Impact of Data Set Construction and Feature Representation.Journal of chemical information and modeling · 2025Article
- Ebola and Marburg virus VP35 coiled-coil validated as antiviral target by tripartite split-GFP complementation.iScience · 2022Article
- Targeting the DENV NS2B-NS3 protease with active antiviral phytocompounds: structure-based virtual screening, molecular docking and molecular dynamics simulation studies.Journal of molecular modeling · 2022Article
- The structural, dynamic, and thermodynamic basis of darunavir resistance of a heavily mutated HIV-1 protease using molecular dynamics simulation.Frontiers in molecular biosciences · 2022Article
- Highly drug-resistant HIV-1 protease reveals decreased intra-subunit interactions due to clusters of mutations.The FEBS journal · 2020Article
- Interactions of the α3β2 Nicotinic Acetylcholine Receptor Interfaces with α-Conotoxin LsIA and its Carboxylated C-terminus Analogue: Molecular Dynamics Simulations.Marine drugs · 2020Article
- Structural and binding insights into HIV-1 protease and P2-ligand interactions through molecular dynamics simulations, binding free energy and principal component analysis.Journal of molecular graphics & modelling · 2019Article
- Recent Developments and Applications of the MMPBSA Method.Frontiers in molecular biosciences · 2017Review
- Conformational variation of an extreme drug resistant mutant of HIV protease.Journal of molecular graphics & modelling · 2015Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Inhibitors of HIV-1 protease (HIV-1-pr) generally only bind to the active site of the protease. However, for some mutants such as V32I and M46L the TMC114 can bind not only to the active cavity but also to the groove of the flexible flaps. Although the second binding site suggests the higher efficiency of the drug against HIV-1-pr, the drug resistance in HIV-1-pr due to mutations cannot be ignored, which prompts us to investigate the molecular mechanisms of drug resistance and behavior of double bound TMC114 (2T) to HIV-1-pr. The conformational dynamics of HIV-1-pr and the binding of TMC114 to the WT, V32I and M46L mutants were investigated with all-atom molecular dynamic (MD) simulation. The 20 ns MD simulation shows many fascinating effects of the inhibitor binding to the WT and mutant proteases. MM-PBSA calculations explain the binding free energies unfavorable for the M46L and V32I mutants as compared to the WT. For the single binding (1T) the less binding affinity can be attributed to the entropic loss for both V32I-1T and M46L-1T. Although the second binding of TMC114 with flap does increase binding energy for the mutants (V32I-2T and M46L-2T), the considerable entropy loss results in the lower binding Gibbs free energies. Thus, binding of TMC114 in the flap region does not help much in the total gain in binding affinity of the system, which was verified from this study and thereby validating experiments.
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