ArticleJournal of the American Chemical Society2017
Can Relative Binding Free Energy Predict Selectivity of Reversible Covalent Inhibitors?
Article in Journal of the American Chemical Society, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed.
- Ligand-Binding Free Energy Simulations of Membrane Proteins.Advances in experimental medicine and biology · 2026Review
- Review
- Advancing Covalent Ligand and Drug Discovery beyond Cysteine.Chemical reviews · 2025Review
- Covalent-Allosteric Inhibitors: Do We Get the Best of Both Worlds?Journal of medicinal chemistry · 2025Review
- Boronic acid inhibitors of penicillin-binding protein 1b: serine and lysine labelling agents.Journal of enzyme inhibition and medicinal chemistry · 2024Article
- Identification and Evaluation of Reversible Covalent Binders to Cys55 of Bfl-1 from a DNA-Encoded Chemical Library Screen.ACS medicinal chemistry letters · 2024Article
- Reversible Covalent Inhibition─Desired Covalent Adduct Formation by Mass Action.ACS chemical biology · 2024Review
- Identification and neuroprotective properties of NA-184, a calpain-2 inhibitor.Pharmacology research & perspectives · 2024Article
- A novel selective ERK1/2 inhibitor, Laxiflorin B, targets EGFR mutation subtypes in non-small-cell lung cancer.Acta pharmacologica Sinica · 2024Article
- Calpain-2 Inhibitors as Therapy for Traumatic Brain Injury.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2023Review
- Reactivity of Covalent Fragments and Their Role in Fragment Based Drug Discovery.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Fast and Effective Prediction of the Absolute Binding Free Energies of Covalent Inhibitors of SARS-CoV-2 Main Protease and 20S Proteasome.Journal of the American Chemical Society · 2022Article
- CHARMM-GUI Free Energy Calculator for Practical Ligand Binding Free Energy Simulations with AMBER.Journal of chemical information and modeling · 2021Article
- Evaluating the covalent binding of carbapenems on BlaC using noncovalent interactions.Journal of molecular modeling · 2021Article
- Fragment-based covalent ligand discovery.RSC chemical biology · 2021Review
- Mechanisms of Proteolytic Enzymes and Their Inhibition in QM/MM Studies.International journal of molecular sciences · 2021Review
- An insight into the interaction between α-ketoamide- based inhibitor and coronavirus main protease: A detailed in silico study.Biophysical chemistry · 2021Article
- CovalentInDB: a comprehensive database facilitating the discovery of covalent inhibitors.Nucleic acids research · 2021Article
- Exploring the Mechanism of Covalent Inhibition: Simulating the Binding Free Energy of α-Ketoamide Inhibitors of the Main Protease of SARS-CoV-2.Biochemistry · 2020Article
- Ranking Reversible Covalent Drugs: From Free Energy Perturbation to Fragment Docking.Journal of chemical information and modeling · 2019Article
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Authors and funding
9 authors.
Funding
Abstract
Reversible covalent inhibitors have many clinical advantages over noncovalent or irreversible covalent drugs. However, apart from selecting a warhead, substantial efforts in design and synthesis are needed to optimize noncovalent interactions to improve target-selective binding. Computational prediction of binding affinity for reversible covalent inhibitors presents a unique challenge since the binding process consists of multiple steps, which are not necessarily independent of each other. In this study, we lay out the relation between relative binding free energy and the overall reversible covalent binding affinity using a two-state binding model. To prove the concept, we employed free energy perturbation (FEP) coupled with λ-exchange molecular dynamics method to calculate the binding free energy of a series of α-ketoamide analogues relative to a common warhead scaffold, in both noncovalent and covalent binding states, and for two highly homologous proteases, calpain-1 and calpain-2. We conclude that covalent binding state alone, in general, can be used to predict reversible covalent binding selectivity. However, exceptions may exist. Therefore, we also discuss the conditions under which the noncovalent binding step is no longer negligible and propose to combine the relative FEP calculations with a single QM/MM calculation of warhead to predict the binding affinity and binding kinetics. Our FEP calculations also revealed that covalent and noncovalent binding states of an inhibitor do not necessarily exhibit the same selectivity. Thus, investigating both binding states, as well as the kinetics will provide extremely useful information for optimizing reversible covalent inhibitors.
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