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   Pages 953 - 966 ( 14 )

Abstract:

<p>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. <p> 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. <p> 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. <p> 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. <p> 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.</p>

Keywords:

Vorasidenib, mIDH1/2, glioma, pharmacophore-based virtual screening, molecular dynamic simulation, ADMET profiling.

Affiliation:

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