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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Computer-Aided Approach for the Discovery of D-Peptides as Inhibitors of SARS-CoV-2 Main Proteas

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Hernandez Gonzalez, Jorge E. [1, 2] ; Eberle, Raphael J. [3, 4] ; Willbold, Dieter [3, 4, 5] ; Coronado, Monika A. [4]
Total Authors: 4
[1] Univ Estadual Paulista UNESP, Multiuser Ctr Biomol Innovat, IBILCE, Sao Jose Do Rio Preto - Brazil
[2] Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Lab Mol Modeling & Dynam, Cidade Univ Ilha Fundao, Rio De Janeiro - Brazil
[3] Heinrich Heine Univ Dusseldorf, Inst Phys Biol, Univ Str, Dusseldorf - Germany
[4] Forschungszentrum Julich, Inst Biol Informat Proc IBI 7, Struct Biochem, Julich - Germany
[5] Forschungszentrum Julich, JuStruct Julich Ctr Struct Biol, Julich - Germany
Total Affiliations: 5
Document type: Journal article
Web of Science Citations: 0

The SARS-CoV-2 main protease, also known as 3-chymotrypsin-like protease (3CL(pro)), is a cysteine protease responsible for the cleavage of viral polyproteins pp1a and pp1ab, at least, at eleven conserved sites, which leads to the formation of mature nonstructural proteins essential for the replication of the virus. Due to its essential role, numerous studies have been conducted so far, which have confirmed 3CL(pro) as an attractive drug target to combat Covid-19 and have reported a vast number of inhibitors and their co-crystal structures. Despite all the ongoing efforts, D-peptides, which possess key advantages over L-peptides as therapeutic agents, have not been explored as potential drug candidates against 3CL(pro). The current work fills this gap by reporting an in silico approach for the discovery of D-peptides capable of inhibiting 3CL(pro) that involves structure-based virtual screening (SBVS) of an in-house library of D-tripeptides and D-tetrapeptides into the protease active site and subsequent rescoring steps, including Molecular Mechanics Generalized-Born Surface Area (MM-GBSA) free energy calculations and molecular dynamics (MD) simulations. In vitro enzymatic assays conducted for the four top-scoring D-tetrapeptides at 20 mu M showed that all of them caused 55-85% inhibition of 3CL(pro) activity, thus highlighting the suitability of the devised approach. Overall, our results present a promising computational strategy to identify D-peptides capable of inhibiting 3CL(pro), with broader application in problems involving protein inhibition. (AU)

FAPESP's process: 20/10214-1 - Integrated computational and experimental strategies for the inhibition of exfoliative toxins from Staphylococcus aureus
Grantee:Jorge Enrique Hernández González
Support Opportunities: Scholarships in Brazil - Post-Doctoral