Computational techniques accelerate drug discovery by identifying bioactive compounds for specific targets, optimizing molecules with moderate activity, or facilitating the repositioning of inactive items onto new targets. Among them, the Inverse Virtual Screening (IVS) approach is aimed at the evaluation of one or a small set of molecules against a panel of targets for addressing target identification. In this work, a focused library of benzothiazole-based compounds was re-investigated by IVS. Four items, originally synthesized and tested on bromodomain-containing protein 9 (BRD9) but yielding poor binding, were critically re-analyzed, disclosing only a partial fit with 3D structure-based pharmacophore models, which, in the meanwhile, were developed for this target. Afterwards, these compounds were re-evaluated through IVS on a panel of proteins involved in inflammation and cancer, identifying soluble epoxide hydrolase (sEH) as a putative interacting target. Three items were subsequently confirmed as able to interfere with sEH activity, leading to inhibition percentages spanning from 70 % up to 30 % when tested at 10 mu M. Finally, one benzothiazole-based compound emerged as the most promising inhibitor featuring an IC50 in the low micromolar range (IC50=6.62 +/- 0.13 mu M). Our data confirm IVS as a predictive tool for accelerating the target identification and repositioning processes.The Inverse Virtual Screening (IVS) approach was used to re-evaluate benzothiazole-based compounds, which were initially designed for bromodomain-containing protein 9 (BRD9) but resulted inactive. Applying the IVS on a customized panel containing proteins involved in cancer and inflammation, the soluble epoxide hydrolase (sEH) was predicted as one of the most promising, aiding the identification of a new sEH inhibitor. image
Repositioning of Small Molecules through the Inverse Virtual Screening in silico Tool: Case of Benzothiazole-Based Inhibitors of Soluble Epoxide Hydrolase (sEH)
Gazzillo E.;Colarusso E.;Giordano A.;Potenza M.;Lauro G.
;Bifulco G.
2024-01-01
Abstract
Computational techniques accelerate drug discovery by identifying bioactive compounds for specific targets, optimizing molecules with moderate activity, or facilitating the repositioning of inactive items onto new targets. Among them, the Inverse Virtual Screening (IVS) approach is aimed at the evaluation of one or a small set of molecules against a panel of targets for addressing target identification. In this work, a focused library of benzothiazole-based compounds was re-investigated by IVS. Four items, originally synthesized and tested on bromodomain-containing protein 9 (BRD9) but yielding poor binding, were critically re-analyzed, disclosing only a partial fit with 3D structure-based pharmacophore models, which, in the meanwhile, were developed for this target. Afterwards, these compounds were re-evaluated through IVS on a panel of proteins involved in inflammation and cancer, identifying soluble epoxide hydrolase (sEH) as a putative interacting target. Three items were subsequently confirmed as able to interfere with sEH activity, leading to inhibition percentages spanning from 70 % up to 30 % when tested at 10 mu M. Finally, one benzothiazole-based compound emerged as the most promising inhibitor featuring an IC50 in the low micromolar range (IC50=6.62 +/- 0.13 mu M). Our data confirm IVS as a predictive tool for accelerating the target identification and repositioning processes.The Inverse Virtual Screening (IVS) approach was used to re-evaluate benzothiazole-based compounds, which were initially designed for bromodomain-containing protein 9 (BRD9) but resulted inactive. Applying the IVS on a customized panel containing proteins involved in cancer and inflammation, the soluble epoxide hydrolase (sEH) was predicted as one of the most promising, aiding the identification of a new sEH inhibitor. imageI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.