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

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.
AbbreviationsCAS
composite active site
CHARMMchemistry at Harvard Macromolecular Mechanics
CUDAcompute unified device architecture
HAThistone acetyletransferase
HDAChistone deacetylase
LARlargazole 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
MDmolecular dynamics
MOEmolecular operating environment
NAMDnanoscale molecular dynamics
NBEnonbonding energy
NBEEelectrostatic nonbonding energy
NBEVVan der Waals nonbonding energy
NBEFnonbonding energy of fragment
NBEFEelectrostatic nonbonding energy of fragment
NBEFVVan der Waals nonbonding energy of fragment
NCnew compound; Rg: radius of gyration;
RMSDroot mean square deviation
RMSFroot mean square fluctuation
VMDvisual molecular dynamics.

composite active site
chemistry at Harvard Macromolecular Mechanics
compute unified device architecture
histone acetyletransferase
histone deacetylase
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
(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)
(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
(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
molecular dynamics
molecular operating environment
nanoscale molecular dynamics
nonbonding energy
electrostatic nonbonding energy
Van der Waals nonbonding energy
nonbonding energy of fragment
electrostatic nonbonding energy of fragment
Van der Waals nonbonding energy of fragment
new compound; Rg: radius of gyration;
root mean square deviation
root mean square fluctuation
visual molecular dynamics.
Communicated by Ramaswamy H. Sarma