The herbicide quinclorac as potent lipase inhibitor: discovery via virtual screening and in vitro/in vivo validation

This study implemented a computational workflow to search for new lipase inhibitory leads by virtually screening commercial agrochemicals against HSL and MGL using 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. 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).

Abstract

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).

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