A multi-pronged approach targeting SARS-CoV-2 proteins using ultra-large virtual screening

被引：62

作者：

Gorgulla, Christoph ^{[1
,2
,3
]}

Das, Krishna M. Padmanabha ^{[1
,3
]}

Leigh, Kendra E. ^{[11
,20
,21
]}

Cespugli, Marco ^{[13
]}

Fischer, Patrick D. ^{[1
,3
,9
]}

Wang, Zi-Fu ^{[1
]}

Tesseyre, Guilhem ^{[4
]}

Pandita, Shreya ^{[4
]}

Shnapir, Alec ^{[4
]}

Calderaio, Anthony ^{[17
]}

Gechev, Minko ^{[4
]}

Rose, Alexander ^{[16
]}

Lewis, Noam ^{[4
]}

Hutcheson, Colin ^{[4
]}

Yaffe, Erez ^{[4
]}

Luxenburg, Roni ^{[4
]}

Herce, Henry D. ^{[1
,3
]}

Durmaz, Vedat ^{[13
]}

Halazonetis, Thanos D. ^{[12
]}

Fackeldey, Konstantin ^{[8
,10
]}

Patten, Justin J. ^{[15
]}

Chuprina, Alexander ^{[5
]}

Dziuba, Igor ^{[19
]}

Plekhova, Alla ^{[6
]}

Moroz, Yurii ^{[6
,7
]}

Radchenko, Dmytro ^{[5
,7
]}

Tarkhanova, Olga ^{[6
]}

Yavnyuk, Irina ^{[5
]}

Gruber, Christian ^{[13
,14
]}

Yust, Ryan ^{[4
]}

Payne, Dave ^{[4
]}

Naar, Anders M. ^{[18
]}

Namchuk, Mark N. ^{[1
]}

Davey, Robert A. ^{[15
]}

Wagner, Gerhard ^{[1
]}

Kinney, Jamie ^{[4
]}

Arthanari, Haribabu ^{[1
,3
]}

机构：

[1] Harvard Univ, Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[2] Harvard Univ, Fac Arts & Sci, Dept Phys, Cambridge, MA 02138 USA

[3] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[4] Google, Mountain View, CA 94043 USA

[5] Enamine, UA-02094 Kiev, Ukraine

[6] Chemspace, UA-02094 Kiev, Ukraine

[7] Taras Shevchenko Natl Univ Kyiv, UA-01601 Kiev, Ukraine

[8] Zuse Inst Berlin ZIB, D-14195 Berlin, Germany

[9] Saarland Univ, Dept Pharm Pharmaceut & Med Chem, D-66123 Saarland, Germany

[10] Tech Univ Berlin, Inst Math, D-10587 Berlin, Germany

[11] Max Planck Inst Biophys, D-60438 Frankfurt, Hessen, Germany

[12] Univ Geneva, Dept Mol Biol, CH-1205 Geneva, Switzerland

[13] Innophore GmbH, A-8010 Graz, Austria

[14] Karl Franzens Univ Graz, Inst Mol Biosci, A-8010 Graz, Austria

[15] Boston Univ, Boston Univ Med Sch, Dept Microbiol, Boston, MA 02118 USA

[16] Mol Consortium, San Diego, CA 92109 USA

[17] VirtualFlow Org, Boston, MA 02115 USA

[18] Univ Calif Berkeley, Dept Nutr Sci & Toxicol, Berkeley, CA 94720 USA

[19] UkrOrgSyntez Ltd, UA-01133 Kiev, Ukraine

[20] Univ Cambridge, Dept Med, Mol Immun Unit, MRC Lab Mol Biol, Cambridge CB2 0QH, England

[21] Univ Cambridge, Dept Med, Cambridge Inst Therapeut Immunol & Infect Dis CIT, Cambridge CB2 0AW, England

来源：

ISCIENCE | 2021年 / 24卷 / 02期

关键词：

RESPIRATORY SYNDROME CORONAVIRUS; PAPAIN-LIKE PROTEASE; SARS-CORONAVIRUS; STRUCTURAL BASIS; RNA-POLYMERASE; SUPRAMOLECULAR ARCHITECTURE; NUCLEOCAPSID PROTEIN; THIOPURINE ANALOGS; MOLECULAR DOCKING; ACCESSORY PROTEIN;

D O I：

10.1016/j.isci.2020.102021

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The unparalleled global effort to combat the continuing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic over the last year has resulted in promising prophylactic measures. However, a need still exists for cheap, effective therapeutics, and targeting multiple points in the viral life cycle could help tackle the current, as well as future, coronaviruses. Here, we leverage our recently developed, ultra-large-scale in silico screening platform, VirtualFlow, to search for inhibitors that target SARS-CoV-2. In this unprecedented structure-based virtual campaign, we screened roughly 1 billion molecules against each of 40 different target sites on 17 different potential viral and host targets. In addition to targeting the active sites of viral enzymes, we also targeted critical auxiliary sites such as functionally important protein-protein interactions.

引用

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