Predicting the Relative Binding Affinity for Reversible Covalent Inhibitors by Free Energy Perturbation Calculations

Author(s)

Bonatto, Vinicius ^[1] ; Shamim, Anwar ^[1] ; Rocho, Fernanda Dos R. ^[1] ; Leitao, Andrei ^[1] ; Luque, F. Javier ^{[2, 3]} ; Lameira, Jeronimo ^{[1, 4]} ; Montanari, Carlos A. ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Chem Sao Carlos, Med & Biol Chem Grp, BR-23566590 Sao Carlos, SP - Brazil

^[2] Univ Barcelona, Fac Pharm & Food Sci, Inst Biomed IBUB, Dept Nutr Food Sci & Gastron, Santa Coloma De Gramenet 08921 - Spain

^[3] Univ Barcelona, Inst Theoret & Computat Chem IQTCUB, Santa Coloma De Gramenet 08921 - Spain

^[4] Fed Univ Para, Inst Biol Sci, Rua Augusto Correa S-N, BR-66075110 Belem, Para - Brazil

• Document type: Journal article
• Source: JOURNAL OF CHEMICAL INFORMATION AND MODELING; v. 61, n. 9, p. 4733-4744, SEP 27 2021.
• Web of Science Citations: 1

Abstract

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. (AU)

• FAPESP's process: 20/04653-2 - Molecular design and synthesis of coronavirus SARS-CoV-2 main protease (SARS CoV-2 Mpro) inhibitors
• Grantee: Carlos Alberto Montanari
• Support Opportunities: Regular Research Grants
• FAPESP's process: 20/06543-0 - Molecular design and synthesis of Coronavirus SARS-CoV-2 main protease (SARS Cov-2 Mpro) inhibitors
• Grantee: Anwar Shamim
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 18/15904-6 - Characterization of cysteine protease inhibitors with antineoplastic activity by in silico and cell-based assays coupled with chemical analyses
• Grantee: Andrei Leitão
• Support Opportunities: Regular Research Grants