Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease

Douangamath, A.; Fearon, D.; Gehrtz, P.; Krojer, T.; Lukacik, P.; Owen, C.D.; Resnick, E.; Strain-Damerell, Claire; Aimon, A.; Ábrányi‐Balogh, Péter; Brandão-Neto, J.; Carbery, A.; Davison, Gemma; Dias, A.; Downes, Thomas D.; Dunnett, L.; Fairhead, M.; Firth, James D.; Jones, Simon P.; Keeley, Aaron; Keserü, György M.; Klein, Hanna F.; Martin, Mathew P.; Noble, M.E.M.; O’Brien, Peter; Powell, A.J.; Reddi, Rambabu N.; Skyner, R.; Snee, M.; Waring, Michael J.; Wild, C.; London, Nir; Delft, F. von; Walsh, Martin A.

doi:10.1038/s41467-020-18709-w

Cited by 466 publications

(579 citation statements)

References 75 publications

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“…Inhibitory fragments used in this work were previously shown to target multiple subpockets within the active M pro site [20]. Therefore, their pharmacophore features were valuable in identifying hits.…”

Section: Discussionmentioning

confidence: 99%

“…Given the urgency for developing effective drugs against COVID-19, Diamond Light Source, UK (www.diamond.ac.uk) performed a crystallographic fragment screening campaign (XChem fragment screen) [20] against SARS-CoV-2 M pro . Of these fragments, 23 were found to be noncovalently bound to the active site of SARS-CoV-2 M pro , 17 of which bound with high confidence.…”

Section: Evaluation Of Zincpharmer Hits Using Molecular Dockingmentioning

confidence: 99%

“…Virtual screening in ZINCPharmer with pharmacophore queries from the 17 fragments known to noncovalently bind to the active centre of SARS-CoV-2 M pro [20] led to the identification of 134 scaffolds belonging to ZINC natural products and their derivative subset. The ZINC library was used as it is a rich source of diverse and often bioactive chemical scaffolds that are commercially available.…”

Section: Identification Of Initial Hits Through Fragment-derived Pharmentioning

confidence: 99%

“…The 3D structures of 17 active fragments (Supporting Information, Figure S1) that were cocrystallised with SARS-CoV-2 M pro as noncovalent binders to its active site in Diamond Light Source M pro XChem Screen [20] were obtained from the PDB. Each fragment was entered as a query into ZINCPharmer [21] to screen a subset of the ZINC database comprising natural products and their derivatives [67] in order to identify molecules with similar pharmacophore features (Figure 7).…”

Section: Virtual Screening With Fragment-based Pharmacophoresmentioning

confidence: 99%

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Novel Small-Molecule Scaffolds as Candidates against the SARS Coronavirus 2 Main Protease: A Fragment-Guided in Silico Approach

et al. 2020

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The ongoing pandemic caused by the novel coronavirus has been the greatest global health crisis since the Spanish flu pandemic of 1918. Thus far, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in over 1 million deaths, and there is no cure or vaccine to date. The recently solved crystal structure of the SARS-CoV-2 main protease has been a major focus for drug-discovery efforts. Here, we present a fragment-guided approach using ZINCPharmer, where 17 active fragments known to bind to the catalytic centre of the SARS-CoV-2 main protease (SARS-CoV-2 Mpro) were used as pharmacophore queries to search the ZINC databases of natural compounds and natural derivatives. This search yielded 134 hits that were then subjected to multiple rounds of in silico analyses, including blind and focused docking against the 3D structure of the main protease. We scrutinised the poses, scores, and protein–ligand interactions of 15 hits and selected 7. The scaffolds of the seven hits were structurally distinct from known inhibitor scaffolds, thus indicating scaffold novelty. Our work presents several novel scaffolds as potential candidates for experimental validation against SARS-CoV-2 Mpro.

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Section: Discussionmentioning

confidence: 99%

Section: Evaluation Of Zincpharmer Hits Using Molecular Dockingmentioning

confidence: 99%

Section: Identification Of Initial Hits Through Fragment-derived Pharmentioning

confidence: 99%

Section: Virtual Screening With Fragment-based Pharmacophoresmentioning

confidence: 99%

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Novel Small-Molecule Scaffolds as Candidates against the SARS Coronavirus 2 Main Protease: A Fragment-Guided in Silico Approach

et al. 2020

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“…PDB codes are (from left to right and top to bottom): 5RFE, 5R7Z, 5R83, 5RET, 5RG3, and 5RHB. As noted by Douangamath et al 1 , overlaying structures suggests many opportunities for fragment merging, for example the two compounds on the left.…”

mentioning

confidence: 82%

Many small steps towards a COVID-19 drug

Erlanson¹

2020

Nat Commun

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Fragment‐based drug discovery—the importance of high‐quality molecule libraries

et al. 2022

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Fragment‐based drug discovery (FBDD) is now established as a complementary approach to high‐throughput screening (HTS). Contrary to HTS, where large libraries of drug‐like molecules are screened, FBDD screens involve smaller and less complex molecules which, despite a low affinity to protein targets, display more ‘atom‐efficient’ binding interactions than larger molecules. Fragment hits can, therefore, serve as a more efficient start point for subsequent optimisation, particularly for hard‐to‐drug targets. Since the number of possible molecules increases exponentially with molecular size, small fragment libraries allow for a proportionately greater coverage of their respective ‘chemical space’ compared with larger HTS libraries comprising larger molecules. However, good library design is essential to ensure optimal chemical and pharmacophore diversity, molecular complexity, and physicochemical characteristics. In this review, we describe our views on fragment library design, and on what constitutes a good fragment from a medicinal and computational chemistry perspective. We highlight emerging chemical and computational technologies in FBDD and discuss strategies for optimising fragment hits. The impact of novel FBDD approaches is already being felt, with the recent approval of the covalent KRASG12C inhibitor sotorasib highlighting the utility of FBDD against targets that were long considered undruggable.

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Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease

Cited by 466 publications

References 75 publications

Novel Small-Molecule Scaffolds as Candidates against the SARS Coronavirus 2 Main Protease: A Fragment-Guided in Silico Approach

Novel Small-Molecule Scaffolds as Candidates against the SARS Coronavirus 2 Main Protease: A Fragment-Guided in Silico Approach

Many small steps towards a COVID-19 drug

Fragment‐based drug discovery—the importance of high‐quality molecule libraries

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