title: Discovery of Covalent Ligands via Noncovalent Docking by Dissecting Covalent Docking Based on a "Steric-Clashes Alleviating Receptor (SCAR)" Strategy.
abstract: Covalent ligands modulating protein activities/signals have attracted unprecedented attention in recent years, but the insufficient understanding of their advantages in the early days of drug discovery has hindered their rational discovery and development. This also left us inadequate knowledge on the rational design of covalent ligands, e.g., how to balance the contribution from the covalent group and the noncovalent group, respectively. In this work, we dissected the noncovalent docking from covalent docking by creating SCARs (steric-clashes alleviating receptors). We showed that the SCAR method outperformed those specifically developed but more complicated covalent docking protocols. We furthermore provided a "proof-of-principle" example by implementing this method in the first high-throughput screening and discovery of novel covalent inhibitors of S-adenosylmethionine decarboxylase. This work demonstrated that noncovalent groups play a predeterminate role in the design of covalent ligands, and would be of great value in accelerating the discovery and development of covalent ligands.
authors.affiliation: Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University , Yichang 443002, China.|College of Medical Science, China Three Gorges University , Yichang 443002, China.
authors.forename: Yuanbao
authors.initials: Y
authors.lastname: Ai
authors.affiliation: Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University , Yichang 443002, China.|College of Medical Science, China Three Gorges University , Yichang 443002, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Yu
authors.affiliation: Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University , Yichang 443002, China.|College of Medical Science, China Three Gorges University , Yichang 443002, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Tan
authors.affiliation: Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University , Yichang 443002, China.|College of Medical Science, China Three Gorges University , Yichang 443002, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Chai
authors.affiliation: Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University , Yichang 443002, China.|College of Medical Science, China Three Gorges University , Yichang 443002, China.
authors.forename: Sen
authors.initials: S
authors.lastname: Liu
mesh_terms: D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D008024:Ligands; D011506:Proteins