Development of New Inhibitors of HDAC1–3 Enzymes Aided by In Silico Design Strategies

Abstract

Histone deacetylases (HDACs) are overexpressed in cancer, and their inhibition shows promising results in cancer therapy. In particular, selective class I HDAC inhibitors such as entinostat are proposed to be more beneficial in breast cancer treatment. Computational drug design is an inevitable part of today's drug discovery projects because of its unequivocal role in saving time and cost. Using three HDAC inhibitors trichostatin, vorinostat, and entinostat as template structures and a diverse fragment library, all synthetically accessible compounds thereof (∼3200) were generated virtually and filtered based on similarity against the templates and PAINS removal. The 298 selected structures were docked into the active site of HDAC I and ranked using a calculated binding affinity. Top-ranking structures were inspected manually, and, considering the ease of synthesis and drug-likeness, two new structures (3a and 3b) were proposed for synthesis and biological evaluation. The synthesized compounds were purified to a degree of more than 95% and structurally verified using various methods. The designed compounds 3a and 3b showed 65−80 and 5% inhibition on HDAC 1, 2, and 3 isoforms at a concentration of 10 μM, respectively. The novel compound 3a may be used as a lead structure for designing new HDAC inhibitors.

Recent updates in click and computational chemistry for drug discovery and development

“…Frontiers in Chemistry frontiersin.org polymerization inhibitor (Dwivedi et al, 2022), PARP-1 inhibitor 2 (Syam et al, 2022), CDK2 inhibitor 3 (Qayed et al, 2022), HDAC-1-3 inhibitor 4 (Cheshmazar et al, 2022), VEGFR-2 inhibitor 5 (Taghour et al, 2022) were identified for cancer therapies. Furthermore, AChE inhibitor 6 (Macedo Vaz et al, 2022) for treatment of Alzheimer's disease and Mtb RNAP inhibitor 7 (Mekonnen Sanka et al, 2022) for antitubercular and antimicrobial treatment were deserve further study.…”

“…To effectively and efficiently design and develop new drugs, computational methods had been applied for drug design including target identification, seeking out and optimizing lead compounds prediction of pharmacokinetic and toxicological properties as well as compound synthesis by molecular docking and molecular dynamics, virtual screening, pharmacophore and ADMET prediction. Novel quinazoline derivative 1 as tubulin polymerization inhibitor ( Dwivedi et al, 2022 ), PARP-1 inhibitor 2 ( Syam et al, 2022 ), CDK2 inhibitor 3 ( Qayed et al, 2022 ), HDAC-1-3 inhibitor 4 ( Cheshmazar et al, 2022 ), VEGFR-2 inhibitor 5 ( Taghour et al, 2022 ) were identified for cancer therapies. Furthermore, AChE inhibitor 6 ( Macedo Vaz et al, 2022 ) for treatment of Alzheimer’s disease and Mtb RNAP inhibitor 7 ( Mekonnen Sanka et al, 2022 ) for antitubercular and antimicrobial treatment were deserve further study.…”

Phenylacetyl-/Trolox- Amides: Synthesis, Sigma-1, HDAC-6, and Antioxidant Activities

“…With the exception of 2, 3, 8, 9, 11, and 13, the remaining compounds are known and reported elsewhere for different applications [24][25][26][27][28][29][30][31][32][33][34][35]. Nonetheless, all 20 compounds were conveniently synthesized in two steps by amidation reactions.…”