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

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 (ΔG_bind) 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; ΔG_bind: −17.21 to −57.42 kcal/mol) in comparison to that of the HDAC8 ligands (NBE: −46.25 to −106.29 kcal/mol; ΔG_bind: −14.74 to −49.52 kcal/mol). From these, NC-VI showed best energy profile (NBE = −126.15 kcal/mol; ΔG_bind = −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 ΔG_bind 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 ΔG_bind profiles by modifying the unfavourable or not so favourable regions of ligands.

Communicated by Ramaswamy H. Sarma

Keywords:

• HDAC8
• MD simulation
• NAMD
• non-bonding energy
• anti-cancer compounds
• vorinostat
• docking

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.