The herbicide quinclorac as potent lipase inhibitor: Discovery via virtual screening and in vitro/in vivo validation
Lina A. Dahabiyeh
Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman, Jordan
Search for more papers by this authorYasser Bustanji
Department of Clinical Pharmacy and Biopharmaceutics, School of Pharmacy, The University of Jordan, Amman, Jordan
Search for more papers by this authorCorresponding Author
Mutasem O. Taha
Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman, Jordan
Correspondence
Mutasem O. Taha, Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Amman, Jordan.
Email: [email protected]
Search for more papers by this authorLina A. Dahabiyeh
Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman, Jordan
Search for more papers by this authorYasser Bustanji
Department of Clinical Pharmacy and Biopharmaceutics, School of Pharmacy, The University of Jordan, Amman, Jordan
Search for more papers by this authorCorresponding Author
Mutasem O. Taha
Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman, Jordan
Correspondence
Mutasem O. Taha, Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Amman, Jordan.
Email: [email protected]
Search for more papers by this authorAbstract
Lipolysis is primarily controlled by the stepwise action of hormone-sensitive lipase (HSL) and monoglyceride lipase (MGL) to release free fatty acids and glycerol. A high level of circulating free fatty acids is well-known to mediate insulin resistance. Thus, the need to discover lipase inhibitors against both enzyme systems remains urgent. Agrochemicals are tightly regulated chemicals and therefore are potential source of new medicinal agents. Accordingly, we implemented a computational workflow to search for new lipase inhibitory leads by virtually screening commercial agrochemicals against HSL and MGL employing binding pharmacophores and docking experiments. Ten agrochemicals were identified as potential lipase inhibitors, out of which quinclorac, a safe herbicide, achieved high-ranking score. Subsequent in vitro evaluation against rat epididymal lipase activity showed quinclorac to exhibit nanomolar anti-lipase IC50. Subsequent in vivo testing showed quinclorac to significantly decrease blood glycerol levels after acute exposure (150 mg/kg) and multiple dosing (50 or 25 mg/kg) (p < 0.05).
CONFLICT OF INTEREST
The authors declare that they have no conflict of interest.
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