Identification of potent histone deacetylase 8 inhibitors using pharmacophore-based virtual screening, three-dimensional quantitative structure–activity relationship, and docking study

Abstract

In recent years, histone deacetylases (HDACs) have been considered one of the promising targets for cancer chemotherapy. In the present study, a six-featured pharmacophore model with two hydrogen bond acceptors (AA), two hydrogen bond donors (DD), and two aromatic rings (RR) was developed. A predictive three-dimensional quantitative structure-activity relationship model was generated using the pharmacophore models obtained. The model has an excellent correlation coefficient and good predictive ability, as shown by the significant statistical parameters for both the training set (R 2 =0.9565, standard deviation =0.1171, F=99, and number of ligands in training set =21) and test set (Q 2 =0.8468, Pearson's R=0.9363, number of ligands in test set =9) molecules. The pharmacophore model was employed for the virtual screening of molecules with HDAC8 activity. The screening resulted in 366 hits with predicted activity as HDAC8 inhibitors. The hits obtained from the virtual screening were subjected to a molecular docking study to identify the potent inhibitors that binds to the active site with high affinity. The molecular docking study of known inhibitors and their analysis showed that the crucial interacting amino acid residues of HDAC8 are TYR-306, HIS-142, PHE-152, TYR-100, HIE-180, PHE-207, and Zn-388. On the basis of fitness score, predicted activities, XP Glide score, ADME results, and interacting amino acid residues, ten structurally diverse hits were reported in this paper as HDAC8 inhibitors.

Structural insight into PRMT5 inhibitors through amalgamating pharmacophore-based virtual screening, ADME toxicity, and binding energy studies to identify new inhibitors by molecular docking

“…2. Hence AADHR pharmacophore model is considered as robust and signi cant out of ve pharmacophore hypotheses [32,33]. Figure 3 shows the geometry of AADHR, two pink colored spheres representing hydrogen bond acceptor (A1, A2), blue colored sphere representing hydrogen bond donor(D5), green colored represents hydrophobic group(H6), orange colored represents aromatic ring(R9).…”

Discovery of novel potential selective HDAC8 inhibitors by combine ligand-based, structure-based virtual screening and in-vitro biological evaluation

“…The HDAC1 grid box was generated selecting active site amino acids ASP-264, ASP-176, and HIS-178 35 . The receptor grid of HDAC8 (PDB ID: 1T64) used in the present study was prepared earlier 32 .…”

“…In the last few decades, the virtual screening tool was employed to identify novel lead molecules with diverse structural features 28–30 . The number of pharmacophore-based virtual screenings for identification of HDAC8 inhibitors against a commercial and in-house database of compounds has been reported to be small 31,32 and the number of 3D QSAR model use for selective HDAC8 inhibitors has been reported to be very limited. This study aimed to find out novel non-hydroxamic acid, selective HDAC8 inhibitors using cost-effective and rapid in silico approach, a combination of pharmacophore-based virtual screening, molecular docking, ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties and evaluation of in vitro HDAC8 and HDAC6 inhibitory activity of identified hits.…”

Pharmacophore Based Virtual Screening and Docking of Different Aryl Sulfonamide Derivatives of 5HT7R Antagonist

“…A stockpile of 61 molecules 9,12-15 , aryl sulfonamide derivatives of (aryloxy) ethyl alicyclic amines compounds (1-2), aryl sulfonamide derivatives of (aryloxy) propyl piperidines compounds (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13), azine sulfonamides of 4-[(2ethyl)piperidinyl-1-yl] phenylpiperazines compounds (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26), quinoline-and isoquinoline-sulfonamides and naphthalene sulfonamides compounds (27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42), quinoline-and isoquinoline-sulfonamides compounds (43-45), azine sulfonamides compounds (46-49) and sulfonamide alkyl (p-xylyl and benzyl) 1-(2-methoxyphenyl)piperazine (o-OMe-PhP) and 1-(2,3-dichlorophenyl)piperazine (2,3-DCPP) compounds (51-61) reported as 5HT7 receptor antagonist, and they were used to develop a three-dimensional pharmacophore model. The IC50 values of these derivatives were converted to the corresponding pIC50.…”

“…Quinoline-and isoquinoline-sulfonamides and naphthalene sulfonamides(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42) …”