title: Pharmacological Analysis of Vorinostat Analogues as Potential Anti-tumor Agents Targeting Human Histone Deacetylases: an Epigenetic Treatment Stratagem for Cancers.
abstract: Alteration of the acetylation status of chromatin and other non-histone proteins by HDAC inhibitors has evolved as an excellent epigenetic strategy in treatment of cancers. The present study was sought to identify compounds with positive pharmacological profiles targeting HDAC1. Analogues of Vorinostat synthesized by Cai et al, 2015 formed the test compounds for the present pharmacological evaluation. Hydroxamte analogue 6H showed superior pharmacological profile in comparison to all the compounds in the analogue dataset owing to its better electrostatic interactions and hydrogen bonding patterns. In order to identify compounds with even better high affinity and pharmacological profile than 6H and Vorinostat, virtual screening was performed. A total of 83 compounds similar to Vorinostat and 154 compounds akin to analogue 6H were retrieved. SCHEMBL15675695 (PubCid: 15739209) and AKOS019005527 (PubCid: 80442147) similar to Vorinostat and 6H, were the best docked compounds among the virtually screened compounds. However, in spite of having good affinity, none of the virtually screened compounds had better affinity than that of 6H. In addition SCHEMBL15675695 was predicted to be a carcinogen while AKOS019005527 is Ames toxic. From, our extensive analysis involving binding affinity analysis, ADMET properties predictions and pharmacophoric mappings, we report Vorinostat hydroxamate analogue 6H to be a potential candidate for HDAC inhibition in treatment of cancers through an epigenetic strategy.
authors.affiliation: Research and Development Centre, Bharathiyar University, Coimbatore, India E-mail : suresh@kufos.ac.in.
authors.forename: Sugathan
authors.initials: S
authors.lastname: Praseetha
authors.forename: Srinivas
authors.initials: S
authors.lastname: Bandaru
authors.forename: Anuraj
authors.initials: A
authors.lastname: Nayarisseri
authors.forename: Sivanpillai
authors.initials: S
authors.lastname: Sureshkumar
mesh_terms: D000107:Acetylation; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D057890:Epigenomics; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors*; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1