Computational Tools for Covalent Drug Design

Professor György M Keserű

Medicinal Chemistry, Research Center for Natural Sciences, Budapest, Hungary

Covalent drugs are electrophilic molecules that bound to the target protein by forming covalent bond with the targeted nucleophilic residue at the binding site. Formerly, covalent inhibitors were typically filtered out in drug discovery programs due to the risk of off-target activity attributed to their reactivity. Few compounds acting by covalent mechanism of action were discovered serendipitously. However, a paradigm change has occurred around the millennium owing to the recognition of distinct therapeutic advantages of covalent inhibition that include potentially full target occupancy and long-action, decoupling pharmacodynamics from pharmacokinetics. Therefore, the rational design of targeted covalent inhibitors (TCIs) has gained increased attention.

The binding of covalent inhibitors follows a two-step mechanism including the first non-covalent binding stage that is the molecular recognition of the non-covalent scaffold. Then the electrophilic functionality of the inhibitor, called warhead reacts with the targeted nucleophilic sidechain of the protein. Here I would focus both steps at two different levels. First I discuss virtual screening applications that allow the prioritization of compounds for experimental testing. After the evaluation of available covalent docking tools [1] we developed new methodologies that allow warhead independent docking of potential covalent inhibitors [2-4]. Next I turned to the accurate prediction of the binding free energy of covalent inhibitors by QM/MM calculations [5]. This approach allows the investigation of the molecular mechanism of action that together with the thermodynamic characterisation facilitate the design of potent covalent inhibitors [6,7].

Recording:

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References:

1. Andrea Scarpino, Gyorgy G Ferenczy and György M Keserű: Comparative Evaluation of Covalent Docking Tools Journal of Chemical Information and Modeling, 2018, 58 (7), 1441-1458.
2. Andrea Scarpino, László Petri, Damijan Knez, Tímea Imre, Péter Ábrányi-Balogh, György G. Ferenczy, Stanislav Gobec and György M. Keserű: WIDOCK: a reactive docking protocol for virtual screening of covalent inhibitors Journal of Computer-Aided Molecular Design, 2021, 35, 223–244.
3. Andrea Scarpino, György G. Ferenczy, György M. Keserű: Binding Mode Prediction and Virtual Screening Applications by Covalent Docking In: Protein-Ligand Interactions and Drug Design (ed. Flavio Ballante), Springer, 2021, pp. 73-88.
4. Moira Rachman, Andrea Scarpino, Dávid Bajusz, Gyula Pálfy, István Vida, András Perczel, Xavier Barril, György M Keserű: DUckCov: a Dynamic Undocking‐based Virtual Screening Protocol for Covalent Binders ChemMedChem, 2019, 14, 1011-1021. 
5. Levente M. Mihalovits, György G. Ferenczy, György M. Keserű: The role of quantum chemistry in covalent inhibitor design International Journal of Quantum Chemistry, 2021, 1-17
6. Levente M. Mihalovits, György G. Ferenczy, György M. Keserű: Affinity and Selectivity Assessment of Covalent Inhibitors by Free Energy Calculations Journal of Chemical Information and Modeling, 2020, 60 (12), 6579-6594.
7. Levente M. Mihalovits, György G. Ferenczy, György M. Keserű: Mechanistic and thermodynamic characterization of oxathiazolones as potent and selective covalent immunoproteasome inhibitors Computational and Structural Biotechnology Journal, 2021, 19, 4486-4496.