Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Hetmann, M; Langner, C; Durmaz, V; Cespugli, M; Köchl, K; Krassnigg, A; Blaschitz, K; Groiss, S; Loibner, M; Ruau, D; Zatloukal, K; Gruber, K; Steinkellner, G; Gruber, CC.
Identification and validation of fusidic acid and flufenamic acid as inhibitors of SARS-CoV-2 replication using DrugSolver CavitomiX
SCI REP-UK. 2023; 13(1): 11783
Doi: 10.1038/s41598-023-39071-z
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- Co-Autor*innen der Med Uni Graz
- Groiss Silvia
- Loibner Martina
- Zatloukal Kurt
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- Abstract:
- In this work, we present DrugSolver CavitomiX, a novel computational pipeline for drug repurposing and identifying ligands and inhibitors of target enzymes. The pipeline is based on cavity point clouds representing physico-chemical properties of the cavity induced solely by the protein. To test the pipeline's ability to identify inhibitors, we chose enzymes essential for SARS-CoV-2 replication as a test system. The active-site cavities of the viral enzymes main protease (M-pro) and papain-like protease (Pl(pro)), as well as of the human transmembrane serine protease 2 (TMPRSS2), were selected as target cavities. Using active-site point-cloud comparisons, it was possible to identify two compounds-flufenamic acid and fusidic acid-which show strong inhibition of viral replication. The complexes from which fusidic acid and flufenamic acid were derived would not have been identified using classical sequence- and structure-based methods as they show very little structural (TM-score: 0.1 and 0.09, respectively) and very low sequence (similar to 5%) identity to M-pro and TMPRSS2, respectively. Furthermore, a cavity-based off-target screening was performed using acetylcholinesterase (AChE) as an example. Using cavity comparisons, the human carboxylesterase was successfully identified, which is a described off-target for AChE inhibitors.