Rational Computational Approaches in Drug Discovery: Potential Inhibitors for Allosteric Regulation of Mutant Isocitrate Dehydrogenase-1 Enzyme in Cancers

被引:3
作者
Thamim, Masthan [1 ]
Agrahari, Ashish Kumar [2 ]
Gupta, Pawan [3 ]
Thirumoorthy, Krishnan [1 ]
机构
[1] Vellore Inst Technol, Sch Adv Sci, Dept Chem, Vellore 632014, Tamil Nadu, India
[2] Translat Hlth Sci & Technol Inst, Faridabad 121001, Haryana, India
[3] Shri Vile Parle Kelavani Mandals Inst Pharm, Dept Pharmaceut Chem, Dhule 424001, Maharashtra, India
来源
MOLECULES | 2023年 / 28卷 / 05期
关键词
chirality; oncometabolite; epigenetics; cancers; 2-Hydroxyglutarate; inhibitors; 3D-QSAR; molecular docking; molecular dynamics simulation; ADME; drug discovery; CADD; MOLECULAR-DYNAMICS; IDH MUTATIONS; MECHANISMS; DOCKING; PROTEIN; DERIVATIVES; METABOLISM; GENERATION; PREDICTION; ACCURACY;
D O I
10.3390/molecules28052315
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Mutations in homodimeric isocitrate dehydrogenase (IDH) enzymes at specific arginine residues result in the abnormal activity to overproduce D-2 hydroxyglutarate (D-2HG), which is often projected as solid oncometabolite in cancers and other disorders. As a result, depicting the potential inhibitor for D-2HG formation in mutant IDH enzymes is a challenging task in cancer research. The mutation in the cytosolic IDH1 enzyme at R132H, especially, may be associated with higher frequency of all types of cancers. So, the present work specifically focuses on the design and screening of allosteric site binders to the cytosolic mutant IDH1 enzyme. The 62 reported drug molecules were screened along with biological activity to identify the small molecular inhibitors using computer-aided drug design strategies. The designed molecules proposed in this work show better binding affinity, biological activity, bioavailability, and potency toward the inhibition of D-2HG formation compare to the reported drugs in the in silico approach.
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页数:29
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