Title:Pharmacophore-based Identification of Potential Mutant Isocitrate Dehydrogenases
I/2 Inhibitors: An Explorative Avenue in Cancer Drug Design
Volume: 23
Issue: 8
Author(s): Preantha Poonan, Xylia Q. Peters, Mahmoud E.S. Soliman*, Mohamed I. Alahmdi and Nader E. Abo-Dya
Affiliation:
- Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville
Campus, Durban 4001, South Africa
Keywords:
Vorasidenib, mIDH1/2, glioma, pharmacophore-based virtual screening, molecular dynamic simulation, ADMET profiling.
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.