452
Views
2
CrossRef citations to date
0
Altmetric
Research Articles

Investigation of HDAC8-ligands’ intermolecular forces through molecular dynamics simulations: profiling of non-bonding energies to design potential compounds as new anti-cancer agents

ORCID Icon, , & ORCID Icon
Pages 4726-4751 | Received 30 Jan 2020, Accepted 04 Jun 2020, Published online: 24 Jun 2020
 

Abstract

Histone deacetylases are zinc-dependent isoform enzymes and play important role in cellular homeostasis. Among these, HDAC8 is a potential anticancer drug target. To design new inhibitors using protein-ligand energy profiles, an all atom molecular dynamics (MD) simulations were carried out on nine HDAC8-ligand co-crystals (PDBs: 1T64, 1T69, 1T67, 3F07, 1W22, 1VKG, 5FCW, 3SFF and 3SFH). TSN, SHH, B3N, AGE, NHB, CRI, 5YA, 0DI and 1DI are ligands of PDBs, respectively. For these HDAC8-ligands, relative Gibbs binding free energy (ΔGbind) from MM/PBSA method and non-bonding energies (NBE) are in agreement with each other (r2=0.678). Therefore, the NBEs are used to analyze ligands’ sub-structures, namely zinc-binding, linker and CAP groups. For linker/CAP regions, this identified carbonyl, amide, and sulfonamide moieties as desirable and alkyl/aryl moieties as electrostatically unfavourable. Using this information, systematically new compounds were designed and subjected to MD simulations. This resulted in seven compounds (NC-I to NC-VII) with encouraging energy profiles (NBE: −76.25 to −127.09 kcal/mol; ΔGbind: −17.21 to −57.42 kcal/mol) in comparison to that of the HDAC8 ligands (NBE: −46.25 to −106.29 kcal/mol; ΔGbind: −14.74 to −49.52 kcal/mol). From these, NC-VI showed best energy profile (NBE = −126.15 kcal/mol; ΔGbind = −57.42 kcal/mol) suggesting its binding affinity and thermodynamic stability. In addition to this, NC-II and NC-III have shown promising NBE and ΔGbind profiles. These may serve as lead molecules for exploration against HDAC8 in cancer therapy. This has provided a basis for designing new compounds with improved NBE and ΔGbind profiles by modifying the unfavourable or not so favourable regions of ligands.

Communicated by Ramaswamy H. Sarma

Disclosure statement

There are no conflict to declare.

Author contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Additional information

Funding

VD thankfully acknowledges the financial support in the form of Senior Research Fellowships from Rajiv Gandhi National Fellowship, University Grants Commission, New Delhi. CSIR-CDRI communication no. 10077.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.