ArticleComputational molecular bioscience2012
Role of Ligand Reorganization and Conformational Restraints on the Binding Free Energies of DAPY Non-Nucleoside Inhibitors to HIV Reverse Transcriptase.
Article in Computational molecular bioscience, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 15 citations in OpenAlex.
- What to Make of Zero: Resolving the Statistical Noise from Conformational Reorganization in Alchemical Binding Free Energy Estimates with Metadynamics Sampling.Journal of chemical theory and computation · 2024Article
- Variational Method for Networkwide Analysis of Relative Ligand Binding Free Energies with Loop Closure and Experimental Constraints.Journal of chemical theory and computation · 2021Article
- Improving Prediction Accuracy of Binding Free Energies and Poses of HIV Integrase Complexes Using the Binding Energy Distribution Analysis Method with Flattening Potentials.Journal of chemical information and modeling · 2018Article
- A combined treatment of hydration and dynamical effects for the modeling of host-guest binding thermodynamics: the SAMPL5 blinded challenge.Journal of computer-aided molecular design · 2017Article
- Free Energy-Based Virtual Screening and Optimization of RNase H Inhibitors of HIV-1 Reverse Transcriptase.ACS omega · 2016Article
- Binding Energy Distribution Analysis Method: Hamiltonian Replica Exchange with Torsional Flattening for Binding Mode Prediction and Binding Free Energy Estimation.Journal of chemical theory and computation · 2016Article
- Parameterization of an effective potential for protein-ligand binding from host-guest affinity data.Journal of molecular recognition : JMR · 2016Article
- A unique binding mode of the eukaryotic translation initiation factor 4E for guiding the design of novel peptide inhibitors.Protein science : a publication of the Protein Society · 2015Article
- BEDAM binding free energy predictions for the SAMPL4 octa-acid host challenge.Journal of computer-aided molecular design · 2015Article
- Virtual screening of integrase inhibitors by large scale binding free energy calculations: the SAMPL4 challenge.Journal of computer-aided molecular design · 2014Article
- Large scale affinity calculations of cyclodextrin host-guest complexes: Understanding the role of reorganization in the molecular recognition process.Journal of chemical theory and computation · 2013Article
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Authors and funding
1 author at 1 institution in 1 country.
Funding
Abstract
The results of computer simulations of the binding of etravirine (TMC125) and rilpivirine (TMC278) to HIV reverse transcriptase are reported. It is confirmed that consistent binding free energy estimates are obtained with or without the application of torsional restraints when the free energies of imposing the restraints are taken into account. The restraints have a smaller influence on the thermodynamics and apparent kinetics of binding of TMC125 compared to the more flexible TMC278 inhibitor. The concept of the reorganization free energy of binding is useful to understand and categorize these effects. Contrary to expectations, the use of conformational restraints did not consistently enhance convergence of binding free energy estimates due to suppression of binding/unbinding pathways and due to the influence of rotational degrees of freedom not directly controlled by the restraints. Physical insights concerning the thermodynamic driving forces for binding and the role of "jiggling" and "wiggling" motion of the ligands are discussed. Based on these insights we conclude that an ideal inhibitor, if chemically realizable, would possess the electrostatic charge distribution of TMC125, so as to form strong interactions with the receptor, and the larger and more flexible substituents of TMC278, so as to minimize reorganization free energy penalties and the effects of resistance mutations, suitably modified, as in TMC125, so as to disfavor the formation of non-binding competent extended conformations when free in solution.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.