Modeling Covalent Protein-Ligand Interactions

Modelagem molecular de inibidores covalentes reversíveis de cisteíno proteases

“…Irreversible warheads pose a challenge in terms of modeling due to the direct relationship between the transition state and the kinetic rate constant (kinact). 61,102,107 Modeling this class of inhibitors requires a more complex approach. In contrast, reversible covalent inhibitors can be more readily modeled using X-ray co-crystalized structures of the inhibitor with the target protein.…”

“…Thus, in certain situations, quantum mechanics-based (QM) methods are required to accurately capture these effects with high accuracy. 61,107 Nonetheless, due to their significant computational demands, QM-based methods are generally avoided in drug discovery projects and are typically restricted to a limited number of atoms. Still, there are situations where QM-based methods can be of interest, such as when determining quantum parameters for developing quantitative structure-activity relationship (QSAR) models.…”

“…Still, there are situations where QM-based methods can be of interest, such as when determining quantum parameters for developing quantitative structure-activity relationship (QSAR) models. 61,107 In this approach, specific descriptors are derived using QM techniques, focusing solely on the studied ligand.…”

“…171 Overall, physics-based methodologies are great choices for modeling noncovalent interactions and accurately assessing energy differences between similar molecules. 61,107 But, studying covalent inhibitors through FEP can be computationally expensive since it requires calculations in both the non-covalent and covalent states.…”