Predicting the Relative Binding Affinity for Reversible Covalent Inhibitors by Free Energy Perturbation Calculations
| Autor: | Fernanda dos Reis Rocho, Jerônimo Lameira, Carlos A. Montanari, Andrei Leitão, Vinícius Bonatto, Anwar Shamim, F. Javier Luque |
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| Rok vydání: | 2021 |
| Předmět: |
chemistry.chemical_classification
Models Molecular Proteases Molecular model Nitrile Drug discovery General Chemical Engineering Entropy General Chemistry Library and Information Sciences Ligands Combinatorial chemistry ENZIMAS Computer Science Applications Free energy perturbation chemistry.chemical_compound Enzyme chemistry Covalent bond Drug Discovery Humans Thermodynamics Entropy (order and disorder) |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| ISSN: | 1549-960X |
| Popis: | Covalent inhibitors are assuming central importance in drug discovery projects, especially in this pandemic scenario. Many research groups have focused their attention on inhibiting viral proteases or human proteases such as cathepsin L (hCatL). The inhibition of these critical enzymes may impair viral replication. However, molecular modeling of covalent ligands is challenging since covalent and noncovalent ligand-bound states must be considered in the binding process. In this work, we evaluated the suitability of free energy perturbation (FEP) calculations as a tool for predicting the binding affinity of reversible covalent inhibitors of hCatL. Our strategy relies on the relative free energy calculated for both covalent and noncovalent complexes and the free energy changes have been compared with experimental data for eight nitrile-based inhibitors, including three new inhibitors of hCatL. Our results demonstrate that the covalent complex can be employed to properly rank the inhibitors. Nevertheless, a comparison of the free energy changes in both noncovalent and covalent states is valuable to interpret the effect triggered by the formation of the covalent bond on the interactions played by functional groups distant from the warhead. Overall, FEP can be employed as a powerful predictor tool in developing and understanding the activity of reversible covalent inhibitors. |
| Databáze: | OpenAIRE |
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