tetano
Editor, Senior Moderator
Sci Rep
. 2023 Jul 21;13(1):11783.
doi: 10.1038/s41598-023-39071-z. Identification and validation of fusidic acid and flufenamic acid as inhibitors of SARS-CoV-2 replication using DrugSolver CavitomiX
M Hetmann[SUP] 1 2 3 [/SUP], C Langner[SUP] 4 [/SUP], V Durmaz[SUP] 1 [/SUP], M Cespugli[SUP] 1 [/SUP], K Köchl[SUP] 1 [/SUP], A Krassnigg[SUP] 1 [/SUP], K Blaschitz[SUP] 1 [/SUP], S Groiss[SUP] 4 [/SUP], M Loibner[SUP] 4 [/SUP], D Ruau[SUP] 5 [/SUP], K Zatloukal[SUP] 4 [/SUP], K Gruber[SUP] 1 2 3 6 [/SUP], G Steinkellner[SUP] 1 2 6 [/SUP], C C Gruber[SUP] 7 8 9 10 [/SUP]
Affiliations
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[SUP]pro[/SUP]) and papain-like protease (Pl[SUP]pro[/SUP]), 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 (~ 5%) identity to M[SUP]pro[/SUP] 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.
. 2023 Jul 21;13(1):11783.
doi: 10.1038/s41598-023-39071-z. Identification and validation of fusidic acid and flufenamic acid as inhibitors of SARS-CoV-2 replication using DrugSolver CavitomiX
M Hetmann[SUP] 1 2 3 [/SUP], C Langner[SUP] 4 [/SUP], V Durmaz[SUP] 1 [/SUP], M Cespugli[SUP] 1 [/SUP], K Köchl[SUP] 1 [/SUP], A Krassnigg[SUP] 1 [/SUP], K Blaschitz[SUP] 1 [/SUP], S Groiss[SUP] 4 [/SUP], M Loibner[SUP] 4 [/SUP], D Ruau[SUP] 5 [/SUP], K Zatloukal[SUP] 4 [/SUP], K Gruber[SUP] 1 2 3 6 [/SUP], G Steinkellner[SUP] 1 2 6 [/SUP], C C Gruber[SUP] 7 8 9 10 [/SUP]
Affiliations
- PMID: 37479788
- PMCID: PMC10362000
- DOI: 10.1038/s41598-023-39071-z
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[SUP]pro[/SUP]) and papain-like protease (Pl[SUP]pro[/SUP]), 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 (~ 5%) identity to M[SUP]pro[/SUP] 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.