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Molecular Simulation Studies of 3,3'-Diindolylmethane as a Potent MicroRNA-21 Antagonist.

ABSTRACT: Objective:In recent decades, the overexpression of microRNA-21 (miR-21) is found to be progressively linked with many diseases such as different types of cancers, cardiovascular diseases, and in?ammation. Thereby, it has become an attractive target for pharmacological and genetic modulation in various diseases, and also for overcoming the resistance to chemotherapy in several cancers. Here, in this study, the role of molecular therapeutics of 3,3'-diindolylmethane (DIM) has been investigated for its ability to bind with the precursor miRNA as a target of miR-21 (hsa-mir-21), which may alter the catalyzation process of dicer, a RNase III enzyme, involved in miRNA transcription. Methods:In this context, the present study describes the potential binding and the structure alteration properties of DIM to precursor miR-21 (pre-miR-21) through Molecular Docking and Molecular Dynamics simulation techniques. Results:As a corollary, DIM formed both non-bonded and covalent interactions with the bases of pre-miR, while covalent interaction with guanine in the 6th position was found to be consensus in molecular dynamics simulation. Furthermore, the stability of both DIM and pre-miR-21 was found to be inversely correlated to each other in binding condition. Conclusion:This result indicates that DIM can be used in target-based therapy and also as a lead for further development of potent small molecule miRNA antagonist.

SUBMITTER: Junaid M

PROVIDER: S-EPMC5810076 | biostudies-literature | 2017 Oct-Dec

REPOSITORIES: biostudies-literature

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Molecular Simulation Studies of 3,3'-Diindolylmethane as a Potent MicroRNA-21 Antagonist.

Junaid Md M Dash Raju R Islam Nazrul N Chowdhury Jui J Alam Md Jahangir MJ Nath Saikat Dev SD Shakil Mohammad Abu Sayem MAS Azam Ashifa A Quader Syed Mustyen SM Zahid Hosen S M SM

Journal of pharmacy & bioallied sciences 20171001 4

<h4>Objective</h4>In recent decades, the overexpression of microRNA-21 (miR-21) is found to be progressively linked with many diseases such as different types of cancers, cardiovascular diseases, and inﬂammation. Thereby, it has become an attractive target for pharmacological and genetic modulation in various diseases, and also for overcoming the resistance to chemotherapy in several cancers. Here, in this study, the role of molecular therapeutics of 3,3'-diindolylmethane (DIM) has been investig ...[more]

PMID: 29456377

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Project description:3,3'-Diindolylmethane (DIM), a major phytochemical derived from ingestion of cruciferous vegetables, is also a dietary supplement. In preclinical models, DIM is an effective cancer chemopreventive agent and has been studied in a number of clinical trials. Previous pharmacokinetic studies in preclinical and clinical models have not reported DIM metabolites in plasma or urine after oral dosing, and the pharmacological actions of DIM on target tissues is assumed to be solely via the parent compound. Seven subjects (6 males and 1 female) ranging from 26-65 years of age, on a cruciferous vegetable-restricted diet prior to and during the study, took 2 BioResponse DIM 150-mg capsules (45.3 mg DIM/capsule) every evening for one week with a final dose the morning of the first blood draw. A complete time course was performed with plasma and urine collected over 48 hours and analyzed by UPLC-MS/MS. In addition to parent DIM, two monohydroxylated metabolites and 1 dihydroxylated metabolite, along with their sulfate and glucuronide conjugates, were present in both plasma and urine. Results reported here are indicative of significant phase 1 and phase 2 metabolism and differ from previous pharmacokinetic studies in rodents and humans, which reported only parent DIM present after oral administration. 3-((1H-indole-3-yl)methyl)indolin-2-one, identified as one of the monohydroxylated products, exhibited greater potency and efficacy as an aryl hydrocarbon receptor agonist when tested in a xenobiotic response element-luciferase reporter assay using Hepa1 cells. In addition to competitive phytochemical-drug adverse reactions, additional metabolites may exhibit pharmacological activity highlighting the importance of further characterization of DIM metabolism in humans. SIGNIFICANCE STATEMENT: 3,3'-Diindolylmethane (DIM), derived from indole-3-carbinol in cruciferous vegetables, is an effective cancer chemopreventive agent in preclinical models and a popular dietary supplement currently in clinical trials. Pharmacokinetic studies to date have found little or no metabolites of DIM in plasma or urine. In marked contrast, we demonstrate rapid appearance of mono- and dihydroxylated metabolites in human plasma and urine as well as their sulfate and glucuronide conjugates. The 3-((1H-indole-3-yl)methyl)indolin-2-one metabolite exhibited significant aryl hydrocarbon receptor agonist activity, emphasizing the need for further characterization of the pharmacological properties of DIM metabolites.

Dataset Information

Molecular Simulation Studies of 3,3'-Diindolylmethane as a Potent MicroRNA-21 Antagonist.

Publications

Molecular Simulation Studies of 3,3'-Diindolylmethane as a Potent MicroRNA-21 Antagonist.

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