ArticleACS chemical biology2012
Extreme entropy-enthalpy compensation in a drug-resistant variant of HIV-1 protease.
Article in ACS chemical biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed.
- Stability-Driven Pose Prediction and Ligand Design via Contact Persistence Analysis from Molecular Dynamics Simulations.Computational and structural biotechnology journal · 2026Article
- Predicting the Impact of Drug Resistance Mutations on Inhibitor Potency with Molecular Dynamics and Machine Learning.The journal of physical chemistry. B · 2025Article
- Dynamic Allostery: Evolution's Double-Edged Sword in Protein Function and Disease.Journal of molecular biology · 2025Review
- Extreme enthalpy‒entropy compensation in the dimerization of small solutes in aqueous solution.European biophysics journal : EBJ · 2024Review
- Enthalpic Classification of Water Molecules in Target-Ligand Binding.Journal of chemical information and modeling · 2024Article
- Prediction of Binding Pose and Affinity of Nelfinavir, a SARS-CoV-2 Main Protease Repositioned Drug, by Combining Docking, Molecular Dynamics, and Fragment Molecular Orbital Calculations.The journal of physical chemistry. B · 2024Article
- Integrative modeling of diverse protein-peptide systems using CABS-dock.PLoS computational biology · 2023Article
- Article
- Electrostatic Interactions between CSTF2 and pre-mRNA Drive Cleavage and Polyadenylation.Biophysical journal · 2022Article
- Revertant mutation V48G alters conformational dynamics of highly drug resistant HIV protease PRS17.Journal of molecular graphics & modelling · 2021Article
- Enthalpy-Entropy Compensation in Biomolecular Recognition: A Computational Perspective.ACS omega · 2021Review
- A synergy of activity, stability, and inhibitor-interaction of HIV-1 protease mutants evolved under drug-pressure.Protein science : a publication of the Protein Society · 2021Article
- An Overview of Human Immunodeficiency Virus-1 Antiretroviral Drugs: General Principles and Current Status.Infection & chemotherapy · 2021Review
- Prediction of HIV drug resistance based on the 3D protein structure: Proposal of molecular field mapping.PloS one · 2021Article
- Viral proteases: Structure, mechanism and inhibition.The Enzymes · 2021Article
- NMR and MD studies combined to elucidate inhibitor and water interactions of HIV-1 protease and their modulations with resistance mutations.Journal of biomolecular NMR · 2019Article
- Characterizing early drug resistance-related events using geometric ensembles from HIV protease dynamics.Scientific reports · 2018Article
- Structural and Thermodynamic Basis of the Enhanced Interaction between Kinesin Spindle Protein Eg5 and STLC-type Inhibitors.ACS omega · 2018Article
- Hydration Structure and Dynamics of Inhibitor-Bound HIV-1 Protease.Journal of chemical theory and computation · 2018Article
- Exploration of the effect of sequence variations located inside the binding pocket of HIV-1 and HIV-2 proteases.Scientific reports · 2018Article
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9 authors.
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Abstract
The development of HIV-1 protease inhibitors has been the historic paradigm of rational structure-based drug design, where structural and thermodynamic analyses have assisted in the discovery of novel inhibitors. While the total enthalpy and entropy change upon binding determine the affinity, often the thermodynamics are considered in terms of inhibitor properties only. In the current study, profound changes are observed in the binding thermodynamics of a drug-resistant variant compared to wild-type HIV-1 protease, irrespective of the inhibitor bound. This variant (Flap+) has a combination of flap and active site mutations and exhibits extremely large entropy-enthalpy compensation compared to wild-type protease, 5-15 kcal/mol, while losing only 1-3 kcal/mol in total binding free energy for any of six FDA-approved inhibitors. Although entropy-enthalpy compensation has been previously observed for a variety of systems, never have changes of this magnitude been reported. The co-crystal structures of Flap+ protease with four of the inhibitors were determined and compared with complexes of both the wild-type protease and another drug-resistant variant that does not exhibit this energetic compensation. Structural changes conserved across the Flap+ complexes, which are more pronounced for the flaps covering the active site, likely contribute to the thermodynamic compensation. The finding that drug-resistant mutations can profoundly modulate the relative thermodynamic properties of a therapeutic target independent of the inhibitor presents a new challenge for rational drug design.
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