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Discovery of DF-461, a Potent Squalene Synthase Inhibitor.

ABSTRACT: We report the development of a new trifluoromethyltriazolobenzoxazepine series of squalene synthase inhibitors. Structure-activity studies and pharmacokinetics optimization on this series led to the identification of compound 23 (DF-461), which exhibited potent squalene synthase inhibitory activity, high hepatic selectivity, excellent rat hepatic cholesterol synthesis inhibitory activity, and plasma lipid lowering efficacy in nonrodent repeated dose studies.

SUBMITTER: Ichikawa M

PROVIDER: S-EPMC4027440 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Discovery of DF-461, a Potent Squalene Synthase Inhibitor.

Ichikawa Masanori M Ohtsuka Masami M Ohki Hitoshi H Ota Masahiro M Haginoya Noriyasu N Itoh Masao M Shibata Yoshihiro Y Ishigai Yutaka Y Terayama Koji K Kanda Akira A Sugita Kazuyuki K

ACS medicinal chemistry letters 20130904 10

We report the development of a new trifluoromethyltriazolobenzoxazepine series of squalene synthase inhibitors. Structure-activity studies and pharmacokinetics optimization on this series led to the identification of compound 23 (DF-461), which exhibited potent squalene synthase inhibitory activity, high hepatic selectivity, excellent rat hepatic cholesterol synthesis inhibitory activity, and plasma lipid lowering efficacy in nonrodent repeated dose studies. ...[more]

PMID: 24900587

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Project description:AimsThe parasite, Leishmania donovani is responsible for lethal visceral leishmaniasis (VL) in humans. There is a need to investigate novel medicines as antileishmanial drugs, as medication currently introduced for leishmaniasis may cause resistance, serious side-effects, chemical instability and high cost. Therefore, this computational study was designed to explore potential phytochemical inhibitors against Leishmania donovani squalene synthase (LdSQS) enzyme, a drug target.Main methodsMultiple sequence alignment was carried to detect conserved regions across squalene synthases from different Leishmania spp. Their evolutionary relationships were studied by generating phylogenetic tree. Homology modeling method was used to build a three dimensional model of the protein. The validated model was explored by docking simulation with the phytochemicals of interest to identify the most potent inhibitors. Two reported inhibitors were used as references in the virtual screening. The top hit compounds (binding energy less than -9 kcal/mol) were further subjected to intermolecular interaction analysis, pharmacophore modeling, pharmacokinetic and toxicity prediction.Key findingsSeven phytochemicals displayed binding energies less than -9 kcal/mol hence demonstrating ability to be strongly bound to the active site of LdSQS to inhibit the enzymatic activity. Ancistrotanzanine B demonstrated the lowest binding affinity of -9.83 kcal/mol superior to reported inhibitors in literature. Conserved two aspartate rich regions and two signatory motifs were found in the L. donovani squalene synthase by multiple sequence alignment. In addition, study of pharmacophore modeling confirmed that top hit phytochemicals and the reported inhibitor (E5700) share common chemical features for their biochemical interaction with LdSQS. Among seven phytochemicals, 3-O-methyldiplacol showed admissible physicochemical, pharmacokinetic and toxicity predictions compared to the reported inhibitors. All seven phytochemicals satisfied in silico prediction criteria for oral bioavailability.SignificanceBased on the current study, these hits can be further structurally optimized and validated under laboratory conditions to develop antileishmanial drugs.

Dataset Information

Discovery of DF-461, a Potent Squalene Synthase Inhibitor.

Publications

Discovery of DF-461, a Potent Squalene Synthase Inhibitor.

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