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.

Identification of High-Affinity Small Molecule Targeting IDH2 for the Clinical Treatment of Acute Myeloid Leukemia

“…(Padmini et al, 2019;Sinha et al, 2019;Palak et al, 2019;Patidar et al, 2016). On the basis of the lowest re-ranking score, the best interacting compound was selected for the further studies (Nayarisseri et al, 2018;Bandaru, 2015b;Praseetha et al, 2016;Mendonça-Junior et al, 2019).…”

Design of PD-L1 inhibitors for lung cancer

“…Furthermore, ligand preparation was done by utilizing the 3D structures of all the constructed as well as the retrieved ligands which were embedded in the LigPrep module of Schrodinger suite, 2013 (Schrodinger. LLC, New York, NY) and were optimized with the help of the OPLS 2005 force field algorithm [21-26]. This preparation gave the ligands in a single file, which was saved with a .sdf extension for docking with the protein crystal structure [27-31].…”

Major Bioactive Prenylated Flavonoids from Humulus lupulus L., Their Applications in Human Diseases and Structure-Activity Relationships (SAR) – A Review

“…98,99 The affinity score of SAHA was compared with similar analogue. 100 SAHA was reported for four with His18, Gly27, Lys31 and Lys331 and five hydrogen bonds with Asp104, His145, His146, Asp181 and Tyr208 to HDAC1 and HDAC2, respectively. For HDAC4 and HDAC6, SAHA showed hydrogen bond interactions with His802, Asp840 and His842, and Gly582 and His614, respectively.…”