期刊
JOURNAL OF CHEMICAL INFORMATION AND MODELING
卷 56, 期 8, 页码 1563-1575出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jcim.6b00334
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资金
- National Natural Science Foundation of China [91330113, 81503355]
- Hubei Province of China [T201203, D20161204]
- China Three Gorges University [KJ2014H015]
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.
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