133
Views
0
CrossRef citations to date
0
Altmetric
Research Article

Exploration of novel hydroxamate zinc binding group inhibitors against HDAC-1-3 enzymes by AI-based virtual screening: atomistic insights from steered molecular dynamics

ORCID Icon, ORCID Icon & ORCID Icon
Received 09 Nov 2023, Accepted 24 Feb 2024, Published online: 08 Mar 2024
 

Abstract

Overexpression of histone deacetylase (HDAC) enzymes is linked to a wide variety of illnesses, including malignancies and neurological disorders, which makes HDAC inhibitors potentially therapeutic. However, most HDAC inhibitors lack subclass or isoform selectivity, which can be dangerous. Featuring both enhanced selectivity and toxicity profiles, slow-binding HDAC inhibitors offer promising treatment options for a variety of disorders. Diseases like cardiac, neurodegenerative disorders and diabetes are mainly associated with the HDAC1, HDAC2 and HDAC3 enzymes. The AI-based virtual screening tool PyRMD is implemented to identify the potential inhibitors from ∼2 million compounds. Based on the IC50 values, the top 10 compounds were selected for molecular docking. From the docking and ADMET study, the top-ranked three compounds were selected for molecular dynamics (MD) simulations. Further, to get more insights into the binding/unbinding mechanism of the ligand, we have employed the steered molecular dynamics (SMD) simulations. This study assists in developing Amber force field parameters for the HDAC1, HDAC2 and HDAC3 proteins and sheds light on the discovery of a potent drug. Our study suggests that hydroxamic acid derivative (i.e. referred to as Comp-1, CHEMBL600072) is the potential inhibitor for the series of HDAC-related diseases.

Communicated by Ramaswamy H. Sarma

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

SMER thanks SRM Institute of Science and Technology (SRM-IST) Research Fellowship for her research work. MP thanks SRM-IST for providing the supercomputing facility and financial support. VR thanks the Department of Science and Technology (DST)-INSPIRE Faculty Award [DST/INSPIRE/04/2016/000131 (IFA-16-CH-233)], New Delhi, India for the financial support.

Log in via your institution

Log in to Taylor & Francis Online

PDF download + Online access

  • 48 hours access to article PDF & online version
  • Article PDF can be downloaded
  • Article PDF can be printed
USD 61.00 Add to cart

Issue Purchase

  • 30 days online access to complete issue
  • Article PDFs can be downloaded
  • Article PDFs can be printed
USD 1,074.00 Add to cart

* Local tax will be added as applicable

Related Research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.