Challenges and Advances in the Simulation of Targeted Covalent Inhibitors Using Quantum Computing.

Targeted covalent inhibitors represent a promising class of drugs that form specific chemical bonds with their biological targets. There are a multitude of molecular systems where covalent inhibitors could address human health challenges. A high-level quantum chemical description of the formation of the critical covalent bond could provide new mechanistic detail and insights into how the mechanism is influenced by the surrounding biomolecular environment. However, accurately simulating the reactivity and binding specificity of such inhibitors remains a significant challenge. By leveraging advances in quantum computing hardware and algorithms, we discuss how quantum computing could benefit the design of targeted covalent inhibitors and enable more accurate simulations of protein-ligand interactions and accelerate de novo drug discovery.