Molecular dynamics simulation of complex Histones Deacetylase (HDAC) Class II Homo Sapiens with suberoylanilide hydroxamic acid (SAHA) and its derivatives as inhibitors of cervical cancer

Abstract

Cervical cancer is second most common cancer in woman worldwide. Cervical cancer caused by human papillomavirus (HPV) oncogene. Inhibition of histone deacetylase (HDAC) activity has been known as a potential strategy for cancer therapy. SAHA is an HDAC inhibitor that has been used in cancer therapy but still has side effects. SAHA modification proposed to minimize side effects. Triazole attachment on the chain of SAHA has been known to enhance the inhibition ability of SAHA and less toxic. In this study, it will be carried out with molecular dynamic simulations of SAHA modifications consisting ligand 1a, 2a and, 2c to interact with six HDAC in hydrated conditions. To all six HDAC Class II, performed docking with SAHA and a modified inhibitor. The docking results were then carried out molecular dynamics simulations to determine the inhibitor affinities in hydrated conditions. The molecular dynamic simulations results show better affinities of ligand 2c with HDAC 4, 6, and 7 than SAHA itself, and good affinity was also shown by ligand 2a and 1c on HDAC 5 and 9. The results of this study can be a reference to obtain better inhibitors.

Utilization of Boron Compounds for the Modification of Suberoyl Anilide Hydroxamic Acid as Inhibitor of Histone Deacetylase Class II Homo sapiens

“…The starting point of the development of our pipeline was the optimization of docking method, which would be improved later on [ 57 ]. Our experience in HPV drug design was based on design of organic compounds as drug candidates [ 46 , 58 ]. However, as carbon and boron based compounds have some similarity of physicochemical properties, the utilization of boron as carbon substitute for drug candidate becomes more feasible [ 59 ].…”

Synergistic combination of histone deacetylase inhibitor suberoylanilide hydroxamic acid and oncolytic adenovirus ZD55-TRAIL as a therapy against cervical cancer

“…ONYX-015, a E1B-55 kDa gene-deleted OA, in combination with chemotherapy has been assessed in phase I-II trials for patients with advanced cancer (26,27). The present study investigated the possibility of combining ZD55-TRAIL with SAHA, an HDAC inhibitor that may be a novel therapeutic agent for patients with cervical squamous cell carcinoma (14)(15)(16)28,29), in order to reinforce their antitumor activities. The present study demonstrated that subclinically achievable doses of SAHA (30), namely, 0.1-0.8 µM, significantly and synergistically increased ZD55-TRAIL oncotoxicity in vitro.…”

The development of novel HPV Drugs by HDAC inhibitor based upon applied bioinformatics tool and their specialized algorithm

“…However, as SAHA has certain side effects, we try to mitigate them by modifying its structure [16]. Hence, we have successfully generated SAHA derivatives and tested them by molecular docking and dynamics tools [27,28]. Hence, we elucidated the molecular interactions of the ligands in high-resolution graphics, as shown in figures 1 [29].…”