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. AbbreviationsCAScomposite active siteCHARMMchemistry at Harvard Macromolecular MechanicsCUDAcompute unified device architectureHAThistone acetyletransferaseHDAChistone deacetylaseLARlargazole 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-trioneL6G(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-trioneL8G(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-trioneMDmolecular dynamicsMOEmolecular operating environmentNAMDnanoscale molecular dynamicsNBEnonbonding energyNBEEelectrostatic nonbonding energyNBEVVan der Waals nonbonding energyNBEFnonbonding energy of fragmentNBEFEelectrostatic nonbonding energy of fragmentNBEFVVan der Waals nonbonding energy of fragmentNCnew compound; Rg: radius of gyration;RMSDroot mean square deviationRMSFroot mean square fluctuationVMDvisual molecular dynamics.Communicated by Ramaswamy H. Sarma.