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A Blueprint for High Affinity SARS-CoV-2 Mpro Inhibitors from Activity-Based Compound Library Screening Guided by Analysis of Protein Dynamics

Gossen, Jonas (författare)
Forschungszentrum Julich, Inst Neurosci & Med INM 9, D-52425 Julich, Germany.;Forschungszentrum Julich, Inst Adv Simulat IAS 5 Computat Biomed, D-52425 Julich, Germany.;Rhein Westfal TH Aachen, Fac Math Comp Sci & Nat Sci, D-52062 Aachen, Germany.
Albani, Simone (författare)
Forschungszentrum Julich, Inst Neurosci & Med INM 9, D-52425 Julich, Germany.;Forschungszentrum Julich, Inst Adv Simulat IAS 5 Computat Biomed, D-52425 Julich, Germany.;Rhein Westfal TH Aachen, Fac Math Comp Sci & Nat Sci, D-52062 Aachen, Germany.
Hanke, Anton (författare)
Heidelberg Inst Theoret Studies HITS, Mol & Cellular Modeling Grp, D-69118 Heidelberg, Germany.;Heidelberg Univ, Inst Pharm & Mol Biotechnol IPMB, D-69120 Heidelberg, Germany.
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Joseph, Benjamin P. (författare)
Forschungszentrum Julich, Inst Neurosci & Med INM 9, D-52425 Julich, Germany.;Forschungszentrum Julich, Inst Adv Simulat IAS 5 Computat Biomed, D-52425 Julich, Germany.;Rhein Westfal TH Aachen, Fac Math Comp Sci & Nat Sci, D-52062 Aachen, Germany.
Bergh, Cathrine (författare)
KTH,SeRC - Swedish e-Science Research Centre,Science for Life Laboratory, SciLifeLab
Kuzikov, Maria (författare)
Fraunhofer Inst Translat Med & Pharmacol ITMP, Dept Screening Port, D-22525 Hamburg, Germany.
Costanzi, Elisa (författare)
Elettra Sincrotrone Trieste SCpA, I-34149 Trieste, Italy.
Manelfi, Candida (författare)
Dompe Farmaceut SpA, I-67100 Laquila, Italy.
Storici, Paola (författare)
Elettra Sincrotrone Trieste SCpA, I-34149 Trieste, Italy.
Gribbon, Philip (författare)
Fraunhofer Inst Translat Med & Pharmacol ITMP, Dept Screening Port, D-22525 Hamburg, Germany.
Beccari, Andrea R. (författare)
Dompe Farmaceut SpA, I-67100 Laquila, Italy.
Talarico, Carmine (författare)
Dompe Farmaceut SpA, I-67100 Laquila, Italy.
Spyrakis, Francesca (författare)
Univ Turin, Dept Drug Sci & Technol, I-10125 Turin, Italy.
Lindahl, Erik (författare)
KTH,Stockholms universitet,Institutionen för biokemi och biofysik,Science for Life Laboratory (SciLifeLab),KTH Royal Institute of Technology, Sweden,SeRC - Swedish e-Science Research Centre,Science for Life Laboratory, SciLifeLab
Zaliani, Andrea (författare)
Fraunhofer Inst Translat Med & Pharmacol ITMP, Dept Screening Port, D-22525 Hamburg, Germany.
Carloni, Paolo (författare)
Forschungszentrum Julich, Inst Neurosci & Med INM 9, D-52425 Julich, Germany.;Forschungszentrum Julich, Inst Adv Simulat IAS 5 Computat Biomed, D-52425 Julich, Germany.;Rhein Westfal TH Aachen, Fac Math Comp Sci & Nat Sci, D-52062 Aachen, Germany.
Wade, Rebecca C. (författare)
Heidelberg Inst Theoret Studies HITS, Mol & Cellular Modeling Grp, D-69118 Heidelberg, Germany.;Heidelberg Univ, Zentrum Molekulare Biol, DKTZ ZMBH Alliance, D-69120 Heidelberg, Germany.;Heidelberg Univ, Interdisciplinary Ctr Sci Comp IWR, D-69120 Heidelberg, Germany.
Musiani, Francesco (författare)
Univ Bologna, Lab Bioinorgan Chem, Dept Pharm & Biotechnol, I-40126 Bologna, Italy.
Kokh, Daria B. (författare)
Heidelberg Inst Theoret Studies HITS, Mol & Cellular Modeling Grp, D-69118 Heidelberg, Germany.
Rossetti, Giulia (författare)
Forschungszentrum Julich, Inst Neurosci & Med INM 9, D-52425 Julich, Germany.;Forschungszentrum Julich, Inst Adv Simulat IAS 5 Computat Biomed, D-52425 Julich, Germany.;Forschungszentrum Julich, Julich Supercomp Ctr JSC, D-52425 Julich, Germany.;Rhein Westfal TH Aachen, Dept Hematol Oncol Hemostaseol & Stem Cell Transp, D-44517 Aachen, Germany.
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Forschungszentrum Julich, Inst Neurosci & Med INM 9, D-52425 Julich, Germany;Forschungszentrum Julich, Inst Adv Simulat IAS 5 Computat Biomed, D-52425 Julich, Germany.;Rhein Westfal TH Aachen, Fac Math Comp Sci & Nat Sci, D-52062 Aachen, Germany. Heidelberg Inst Theoret Studies HITS, Mol & Cellular Modeling Grp, D-69118 Heidelberg, Germany.;Heidelberg Univ, Inst Pharm & Mol Biotechnol IPMB, D-69120 Heidelberg, Germany. (creator_code:org_t)
2021-03-16
2021
Engelska.
Ingår i: ACS Pharmacology & Translational Science. - : American Chemical Society (ACS). - 2575-9108. ; 4:3, s. 1079-1095
Relaterad länk:
https://doi.org/10.1...
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https://pubs.acs.org...
https://urn.kb.se/re...
https://doi.org/10.1...
https://urn.kb.se/re...
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
Stäng  
  • The SARS-CoV-2 coronavirus outbreak continues to spread at a rapid rate worldwide. The main protease (Mpro) is an attractive target for anti-COVID-19 agents. Unexpected difficulties have been encountered in the design of specific inhibitors. Here, by analyzing an ensemble of similar to 30 000 SARS-CoV-2 Mpro conformations from crystallographic studies and molecular simulations, we show that small structural variations in the binding site dramatically impact ligand binding properties. Hence, traditional druggability indices fail to adequately discriminate between highly and poorly druggable conformations of the binding site. By performing similar to 200 virtual screenings of compound libraries on selected protein structures, we redefine the protein's druggability as the consensus chemical space arising from the multiple conformations of the binding site formed upon ligand binding. This procedure revealed a unique SARS-CoV-2 Mpro blueprint that led to a definition of a specific structure-based pharmacophore. The latter explains the poor transferability of potent SARS-CoV Mpro inhibitors to SARS-CoV-2 Mpro, despite the identical sequences of the active sites. Importantly, application of the pharmacophore predicted novel high affinity inhibitors of SARS-CoV-2 Mpro, that were validated by in vitro assays performed here and by a newly solved X-ray crystal structure. These results provide a strong basis for effective rational drug design campaigns against SARS-CoV-2 Mpro and a new computational approach to screen protein targets with malleable binding sites.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
NATURVETENSKAP  -- Biologi (hsv//swe)
NATURAL SCIENCES  -- Biological Sciences (hsv//eng)
NATURVETENSKAP  -- Kemi -- Organisk kemi (hsv//swe)
NATURAL SCIENCES  -- Chemical Sciences -- Organic Chemistry (hsv//eng)

Nyckelord

conformational space
druggability
Mpro
molecular dynamics simulation
virtual screening
protein binding site flexibility
SARS-CoV-2

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