MD simulations for rational design of high-affinity HDAC4 inhibitors - Analysis of non-bonding interaction energies for building new compounds.

Autor: Dewaker V; Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, 226017, India., Srivastava PN; Molecular Parasitology and Immunology Division, CSIR-Central Drug Research Institute, Lucknow, 226017, India., Debnath U; School of Health Sciences and Technology, UPES, Dehradun, 246007, India., Srivastava AK; Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, 226017, India., Prabhakar YS; Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, 226017, India. Electronic address: yenpra@yahoo.com.
Jazyk: angličtina
Zdroj: Archives of biochemistry and biophysics [Arch Biochem Biophys] 2024 Dec 09; Vol. 764, pp. 110262. Date of Electronic Publication: 2024 Dec 09.
DOI: 10.1016/j.abb.2024.110262
Abstrakt: This study investigates the contributions of non-bonding energy (NBE) to the efficacy of four HDAC4 co-crystallized inhibitors (HA3, 9F4, EBE, and TFG) through 100ns Molecular Dynamics (MD) simulations. These inhibitors contain hydroxamic acid (HA3, 9F4, EBE) or diol (TFG) as zinc-binding groups. In PDBs 2VQJ and 2VQM, the HDAC4 catalytic domain is in the 'open' conformation, while in PDBs 4CBT and 6FYZ, the same is in the 'closed' conformation. We identified HA3 as a weaker inhibitor because of the unfavorable NBE contributions from its carbonyl fragment (FR3) and hydroxamic fragment (FR1). To enhance NBE efficacy, we designed novel HA3 analogs (H01-H16) by introducing diverse fragments (-CF3, 2-hydroxyacetic acid, -NH-CH2-, 5-fluoro-2-phenyl pyrimidine, and chloroquinoline moieties). MD simulations revealed promising analogs (H02, H07, H08, H15) with strong NBEs and stable ligand-zinc retention (2.07-2.33 Å). These analogs exhibited strong relative binding free energies within their catalytic sites, highlighting their potential as novel HDAC4 inhibitors. The current study provides medicinal chemists with insights into non-covalent interactions, identifies key fragments for optimization, and offers a rational design strategy for developing more effective HDAC4 inhibitors.
Competing Interests: Competing interests There are no conflicts to declare.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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