Molecular dynamics study of HDAC8-largazole analogues co-crystals for designing potential anticancer compounds

Abstract

The X-ray crystal structures of HDAC8 complexed with largazole thiol (LAR, PubChem CID: 56663191) and its synthetic variants (Ligand ID in PDB, PubChem CID: L6G, 91667418; L7G, 91667421; L8G, 91667420) (PDB codes: 3RQD, 4RN0, 4RN2 and 4RN1) were analyzed using molecular dynamics simulations to comprehend protein-ligand nonbonding energies (NBEs). The NBEs of ligands’ substructures vis-à-vis active site indicated that pyridyl fragment (F2B4) in L7G and L8G, and amide fragment (F2B5) in LAR and L6G are in high energy states. Based on ligands’ substructures and active site residues properties new compounds were designed by introducing phenolic and amidine moieties, respectively, for F2B4 and F2B5. This improved NBEs of new compounds (NC2, –60.93 kcal/mol; NC3, -42.42 kcal/mol). Also, Zn²⁺ group (substructure F1) of largazoles was modified with that of SAHA and Trapoxin A. Here, the results indicated in favor of Zn²⁺ group of Trapoxin A. New compound NC6 incorporating aforesaid modifications i.e. phenolic moiety for F2B4, amidine moiety for F2B5 and Zn²⁺ group of Trapoxin A in F1, offered best interactions with HDAC8 (–89.75 kcal/mol). Thus, the study revealed new depsipeptides as potential HDAC8 inhibitors.

Abbreviations
CAS	=	composite active site
CHARMM	=	chemistry at Harvard Macromolecular Mechanics
CUDA	=	compute unified device architecture
HAT	=	histone acetyletransferase
HDAC	=	histone deacetylase
LAR	=	largazole thiol (or) (2R,5R,8R,11R)-5-methyl-8-(propan-2-yl)-11-[(1E)-4-sulfanylbut-1-en-1-yl]-10-oxa-3,17-dithia-7,14,19,20-tetraazatricyclo[14.2.1.1 ∼ 2,5∼]icosa-1(18),16(19)-diene-6,9,13-trione
L6G	=	(5R, 8S,11S)-5-methyl-8-(propan-2-yl)-11-[(1E)-4-sulfanylbut-1-en-1-yl]-3,17-dithia-7,10,14,19,20-pentaazatricyclo[14.2.1.1 ∼ 2,5∼]icosa-1(18),2(20),16(19)-triene-6,9,13-trione)
L7G	=	(5R,8S,11S)-5-methyl-8-(propan-2-yl)-11-[(1E)-4-sulfanylbut-1-en-1-yl]-3-thia-7,10,14,17,21-pentaazatricyclo[14.3.1.1 ∼ 2,5∼]henicosa-1(20),2 (21),16,18-tetraene-6,9,13-trione
L8G	=	(5R,8S,11S)-5-methyl-8-(propan-2-yl)-11-[(1E)-4-sulfanylbut-1-en-1-yl]-3-thia-7,10,14,20,21-pentaazatricyclo[14.3.1.1 ∼ 2,5∼]henicosa-1(20),2(21),16,18-tetraene-6,9,13-trione
MD	=	molecular dynamics
MOE	=	molecular operating environment
NAMD	=	nanoscale molecular dynamics
NBE	=	nonbonding energy
NBEE	=	electrostatic nonbonding energy
NBEV	=	Van der Waals nonbonding energy
NBEF	=	nonbonding energy of fragment
NBEFE	=	electrostatic nonbonding energy of fragment
NBEFV	=	Van der Waals nonbonding energy of fragment
NC	=	new compound; Rg: radius of gyration;
RMSD	=	root mean square deviation
RMSF	=	root mean square fluctuation
VMD	=	visual molecular dynamics.

Communicated by Ramaswamy H. Sarma

Keywords:

• HDAC8
• largazole thiol
• romidepsin
• MD simulation
• NAMD
• nonbonding energy
• docking

Disclosure statement

There are no conflicts to declare.

Additional information

Funding

V.D. and P.N.S. thankfully acknowledges the financial support in the form of Senior Research Fellowships from Rajiv Gandhi National Fellowship, University Grants Commission, New Delhi and Department of Biotechnology, Government of India, New Delhi, respectively. CDRI Communication No.:9822.