In Silico Design and Optimisation of Phytoalexin Resveratrol Polyphenolic Analogs as Inhibitors of Histone Acetyltransferase for the Management of Tumor Growth
Journal Title: UNKNOWN - Year 2018, Vol 8, Issue 8
Abstract
Cancer cells are known to be more susceptible to deoxyribonucleic acid (DNA) damage than normal ones due to their genetic instability. The post-translation modification of histones plays a crucial role in chromatin regulation, influencing gene expression, DNA replication and repair. Histone acetyl transferases (HAT) are enzymes that acetylate histones, often resulting in increased gene expression and cellular proliferation. Consequently, modulators of HAT have the potential to be promising chemotherapeutic agents, due to their ability to restrict neoplastic cellular proliferation and DNA repair.Literature suggests that resveratrol’s anti-cancerous effects are a result of its inhibition of histone deacetylases, however, despite the promising efficacy of the anti-proliferative effects documented in both in vitro and in vivo studies, the precise mechanism of action of resveratrol’s capability to suppress tumor growth is still under investigation. This study has consequently considered resveratrol from a different perspective, and has used this seemingly applicable molecule as a potential ligand for the p300-HAT enzyme and thus, has investigated its potential to modulate the p300-HAT ligand binding pocket (p300-HAT_LBP), a protein which is implicated in the epigenetic evolution of many epithelial and haematological malignancies. Superior novel inhibitors were designed through a dual-methodology, comprising of de novo and virtual screening drug design approaches.Two structures, identified through virtual screening, specifically, Chembridge_5190757 and IBS-STOCK1N-57915, and one de novo generated structure, Result_133, that satisfied all measured parameters of Lipinski rule compliance, high ligand binding affinity and predicted safety upon oral administration, were identified for optimisation and in vitrovalidation, on the premise that they hold promise as clinically useful anti-neoplastic agen
Authors and Affiliations
Rebecca Hammet, Clarie Shoemak
Keywords
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