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Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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Research Article

Pharmacophore-based Identification of Potential Mutant Isocitrate Dehydrogenases I/2 Inhibitors: An Explorative Avenue in Cancer Drug Design

Author(s): Preantha Poonan, Xylia Q. Peters, Mahmoud E.S. Soliman*, Mohamed I. Alahmdi and Nader E. Abo-Dya

Volume 23, Issue 8, 2023

Published on: 11 January, 2023

Page: [953 - 966] Pages: 14

DOI: 10.2174/1871520623666221129163001

Price: $65

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Abstract

Background: Heterozygous mutations in the cytoplasmic and mitochondrial isoforms of isocitrate dehydrogenase enzymes 1 and 2 subtypes have been extensively exploited as viable druggable targets, as they decrease the affinity of isocitrate and higher affinity of D-2-hydroxyglutarate, an oncometabolite.

Objective: Vorasidenib (AG-881) has recently been reported as a promising dual inhibitor of mutant isocitrate dehydrogenase 1 and 2 with the ability to penetrate the blood-brain barrier towards the treatment of low-grade glioma. In order to combat drug resistance and toxicity levels, this compelled us to further investigate this substance as a basis for the creation of potential selective inhibitors of mutant isocitrate dehydrogenases 1 and 2.

Methods: By employing a wide range of computational techniques, binding moieties of AG-881 that contributed towards its selective binding to isocitrate dehydrogenase enzymes 1 and 2 were identified and subsequently used to generate pharmacophore models for the screening of potential inhibitor drugs that were further assessed by their pharmacokinetics and physicochemical properties.

Results: AG-881 was identified as the most favorable candidate for isocitrate dehydrogenase enzyme 1, exhibiting a binding free energy of -28.69 kcal/mol. ZINC93978407 was the most favorable candidatefor isocitrate dehydrogenase enzyme 2, displaying a strong binding free energy of -27.10 kcal/mol. ZINC9449923 and ZINC93978407 towards isocitrate dehydrogenase enzyme 1 and 2 showed good protein structural stability with a low radius of gyration values relative to AG-881.

Conclusion: We investigated that ZINC9449923 of isocitrate dehydrogenase enzyme 1 and ZINC 93978407 of isocitrate dehydrogenase enzyme 2 could serve as promising candidates for the treatment of lower-grade glioma as they cross the blood-brain barrier, and present with lower toxicity levels relative to AG-881.

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