1. Development of potent dipeptide-type SARS-CoV 3CL protease inhibitors with novel P3 scaffolds: Design, synthesis, biological evaluation, and docking studies.
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Thanigaimalai, Pillaiyar, Konno, Sho, Yamamoto, Takehito, Koiwai, Yuji, Taguchi, Akihiro, Takayama, Kentaro, Yakushiji, Fumika, Akaji, Kenichi, Chen, Shen-En, Naser-Tavakolian, Aurash, Schön, Arne, Freire, Ernesto, and Hayashi, Yoshio
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STRUCTURE-activity relationship in pharmacology , *PROTEASE inhibitors , *DIPEPTIDES , *PROTEOLYTIC enzymes , *MOLECULAR docking , *DRUG design , *DRUG synthesis - Abstract
Abstract: We report the design and synthesis of a series of dipeptide-type inhibitors with novel P3 scaffolds that display potent inhibitory activity against SARS-CoV 3CLpro. A docking study involving binding between the dipeptidic lead compound 4 and 3CLpro suggested the modification of a structurally flexible P3 N-(3-methoxyphenyl)glycine with various rigid P3 moieties in 4. The modifications led to the identification of several potent derivatives, including 5c–k and 5n with the inhibitory activities (K i or IC50) in the submicromolar to nanomolar range. Compound 5h, in particular, displayed the most potent inhibitory activity, with a K i value of 0.006 μM. This potency was 65-fold higher than the potency of the lead compound 4 (K i = 0.39 μM). In addition, the K i value of 5h was in very good agreement with the binding affinity (16 nM) observed in isothermal titration calorimetry (ITC). A SAR study around the P3 group in the lead 4 led to the identification of a rigid indole-2-carbonyl unit as one of the best P3 moieties (5c). Further optimization showed that a methoxy substitution at the 4-position on the indole unit was highly favorable for enhancing the inhibitory potency. [Copyright &y& Elsevier]
- Published
- 2013
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