Galeon: A Biologically Active Molecule with In Silico Metabolite Prediction, In Vitro Metabolic Profiling in Rat Liver Microsomes, and In Silico Binding Mechanisms with CYP450 Isoforms.

A F M Motiur Rahman,Wencui Yin,Yurngdong Jahng,Adnan A Kadi

doi:10.3390/molecules25245903

A F M Motiur Rahman, Wencui Yin + Show 2 more

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https://doi.org/10.3390/molecules25245903

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Abstract

Galeon, a natural cyclic-diarylheptanoid (CDH), which was first isolated from Myrica gale L., is known to have potent cytotoxicity against A549 cell lines, anti-tubercular activity against Mycobacterium tuberculosis H37Rv, chemo-preventive potential, and moderate topoisomerase inhibitory activity. Here, in silico metabolism and toxicity prediction of galeon by CYP450, in vitro metabolic profiling study in rat liver microsomes (RLMs), and molecular interactions of galeon-CYP450 isoforms were performed. An in silico metabolic prediction study showed demethyl and mono-hydroxy galeon were the metabolites with the highest predictability. Among the predicted metabolites, mono-hydroxy galeon was found to have plausible toxicities such as skin sensitization, thyroid toxicity, chromosome damage, and carcinogenicity. An in vitro metabolism study of galeon, incubated in RLMs, revealed eighteen Phase-I metabolites, nine methoxylamine, and three glutathione conjugates. Identification of possible metabolites and confirmation of their structures were carried out using ion-trap tandem mass spectrometry. In silico docking analysis of galeon demonstrated significant interactions with active site residues of almost all CYP450 isoforms.

Highlights

Metabolic profiling of known/unknown and natural/synthetic molecules has become attractive to scientists due to the fact of its importance in drug discovery and development
We found that galeon maximum galeon interacts interactswith withthe theactive activesite siteofof
We found that the CYP3A4 isoform showed the highest metabolic showed a measurable amount of enzymatic activity against galeon

Summary

Introduction

Metabolic profiling of known/unknown and natural/synthetic molecules has become attractive to scientists due to the fact of its importance in drug discovery and development. Drug metabolism can generate chemically reactive metabolites which are, in most cases, responsible for the unexpected toxicities of a drug, as they tend to react with cellular components [1,2], such as DNA and proteins, leading to mutagenicity, teratogenicity or carcinogenicity [3]. This is a major issue for patient safety and sometimes leads to drug withdrawals or use restriction. A large number of natural/synthetic molecules have been reported to have potent biological activities, their further development is hampered due to the fact of their poor bioavailability

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