Browse
Submit Data
Databases
API
Help

Dataset Information

27 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Computational Approaches for the Design of Novel Anticancer Compounds Based on Pyrazolo[3,4-d]pyrimidine Derivatives as TRAP1 Inhibitor.

ABSTRACT: In the present in-silico study, various computational techniques were applied to determine potent compounds against TRAP1 kinase. The pharmacophore hypothesis DHHRR_1 consists of important features required for activity. The 3D QSAR study showed a statistically significant model with R² = 0.96 and Q² = 0.57. Leave one out (LOO) cross-validation (R² CV = 0.58) was used to validate the QSAR model. The molecular docking study showed maximum XP docking scores (-11.265, -10.532, -10.422, -10.827, -10.753 kcal/mol) for potent pyrazole analogs (42, 46, 49, 56, 43), respectively, with significant interactions with amino acid residues (ASP 594, CYS 532, PHE 583, SER 536) against TRAP1 kinase receptors (PDB ID: 5Y3N). Furthermore, the docking results were validated using the 100 ns MD simulations performed for the selected five docked complexes. The selected inhibitors showed relatively higher binding affinities than the TRAP1 inhibitor molecules present in the literature. The ZINC database was used for a virtual screening study that screened ZINC05297837, ZINC05434822, and ZINC72286418, which showed similar binding interactions to those shown by potent ligands. Absorption, distribution, metabolism, and excretion (ADME) analysis showed noticeable results. The results of the study may be helpful for the further development of potent TRAP1 inhibitors.

SUBMITTER: Ali A

PROVIDER: S-EPMC8512242 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Design, Synthesis, and Anticancer Screening for Repurposed Pyrazolo[3,4-d]pyrimidine Derivatives on Four Mammalian Cancer Cell Lines.

Project description:The present study reports the synthesis of new purine bioisosteres comprising a pyrazolo[3,4-d]pyrimidine scaffold linked to mono-, di-, and trimethoxy benzylidene moieties through hydrazine linkages. First, in silico docking experiments of the synthesized compounds against Bax, Bcl-2, Caspase-3, Ki67, p21, and p53 were performed in a trial to rationalize the observed cytotoxic activity for the tested compounds. The anticancer activity of these compounds was evaluated in vitro against Caco-2, A549, HT1080, and Hela cell lines. Results revealed that two (5 and 7) of the three synthesized compounds (5, 6, and 7) showed high cytotoxic activity against all tested cell lines with IC50 values in the micro molar concentration. Our in vitro results show that there is no significant apoptotic effect for the treatment with the experimental compounds on the viability of cells against A549 cells. Ki67 expression was found to decrease significantly following the treatment of cells with the most promising candidate: drug 7. The overall results indicate that these pyrazolopyrimidine derivatives possess anticancer activity at varying doses. The suggested mechanism of action involves the inhibition of the proliferation of cancer cells.

| S-EPMC8156061 | biostudies-literature

Water Solubility Enhancement of Pyrazolo[3,4-d]pyrimidine Derivatives via Miniaturized Polymer-Drug Microarrays.

Project description:A miniaturized assay was optimized to evaluate the enhanced apparent water solubility of pyrazolo[3,4-d]pyrimidine derivatives used extensively as anticancer drug scaffolds. The applied amount of drugs used in the reported strategy ranged from 5 to 10 ?g per formulation which were dispensed by an inkjet 2D printer directly into a 96-well plate. The selected polymer/drug formulations with high water solubility demonstrated improved cytotoxicity against a human lung adenocarcinoma cancer cell line (A549) compared to the free drugs. We attribute the enhanced efficacy to the improved apparent-solubility of the drug molecules achieved via this methodology. This novel miniaturized method showed promising results in terms of water solubility improvement of the highly hydrophobic pyrazolo[3,4-d]pyrimidine derivatives, requiring only a few micrograms of each drug per tested polymeric formulation. In addition, the reported experimental evidence may facilitate identification of suitable polymers for combination with drug, leading to investigations on biological properties or mechanisms of action in a single formulation.

| S-EPMC5846050 | biostudies-literature

Four-component bicyclization approaches to skeletally diverse pyrazolo[3,4-b]pyridine derivatives.

Project description:A novel four-component bicyclization strategy has been established, allowing a flexible and practical approach to 37 examples of multicyclic pyrazolo[3,4-b]pyridines from low-cost and readily accessible arylglyoxals, pyrazol-5-amines, aromatic amines, 4-hydroxy-6-methyl-2H-pyran-2-one, and cyclohexane-1,3-diones. The polysubstituted cyclopenta[d]pyrazolo[3,4-b]pyridines were stereoselectively synthesized through a microwave-assisted special [3+2+1]/[3+2] bicyclization with good control of the spatial configuration of exocyclic double bonds. The novel [3+2+1]/[2+2+1] bicyclization resulted in 17 examples of unreported pyrazolo[3,4-b]pyrrolo[4,3,2-de]quinolones. Reasonable mechanisms for forming two new types of multicyclic pyrazolo[3,4-b]pyridines are also proposed.

| S-EPMC4242041 | biostudies-literature

4-Hydrazino-1-methyl-pyrazolo[3,4-d]pyrimidine.

Project description:The title compound, C(6)H(8)N(6), crystallizes as an N-H?N hydrogen-bond-linked dimer of two almost identical mol-ecules in the asymmetric unit. Both of the mol-ecules are almost planar (rms deviations of 0.0186 and 0.0296?Å in the two molecules) and their hydrazino groups are turned towards the pyrazole rings. The dimers are arranged into chains via inter-molecular N-H?N hydrogen bonds between the hydrazino groups and the N atoms of the pyrimidine rings of both types of the mol-ecules, linking the mol-ecules into a C(7) graph-set motif along [100]. The methyl groups and the N atoms of the pyrazole rings form weak C-H?N hydrogen bonds, which connect chains of the dimers in a C(4) motif parallel to [100].

| S-EPMC2977168 | biostudies-literature

4-Benzyl-sulfanyl-1H-pyrazolo-[3,4-d]pyrimidine.

Project description:The pyrazolo-[3,4-d]pyrimidine ring system of the title compound, C12H10N4S, is essentially planar [maximum deviation = 0.025?(1)?Å for the C atom bearing the S atom] and almost perpendicular to the phenyl ring [dihedral angle = 71.42?(6)°]. In the crystal, mol-ecules are linked via pairs of N-H?N hydrogen bonds, forming inversion dimers.

| S-EPMC3884315 | biostudies-literature

A Pyrazolo[3,4-d]Pyrimidine compound (a Fyn inhibitor) induces apoptosis and cell death in Large Granular Lymphocyte Leukemia cells

Project description:KHYG1 cell line (NK leukemia) were treated with a new compound, a pyrazolo[3,4-d]Pyrimidine. This compound induces apoptosis and cell death in this cell line. The mechanisms of apoptosis and cell death were investigated. A gene expression profile was used as support.

2016-10-03 | E-MTAB-4536 | biostudies-arrayexpress

Discovery of new 1H-pyrazolo[3,4-d]pyrimidine derivatives as anticancer agents targeting EGFRWT and EGFRT790M.

Project description:New 1H-pyrazolo[3,4-d]pyrimidine derivatives were designed and synthesised to act as epidermal growth factor receptor inhibitors (EGFRIs). The synthesised derivatives were assessed for their in vitro anti-proliferative activities against A549 and HCT-116 cancer cells. Compounds 8, 10, 12a, and 12b showed potent anti-proliferative activities. Compound 12b was the most promising member with IC50 values of 8.21 and 19.56 µM against A549 and HCT-116, respectively. Compounds 8, 10, 12a, and 12b were evaluated for their kinase inhibitory activities against wild EGFR (EGFRWT). Compound 12b was the most potent member showing an IC50 value of 0.016 µM. In addition, compound 12b showed noticeable activity against mutant EGFR (EGFRT790M) (IC50 = 0.236 µM). Flow cytometric analyses revealed that compound 12b is a good apoptotic inducer and can arrest the cell cycle at S and G2/M phases. Furthermore, it produced an 8.8-fold increase in BAX/Bcl-2 ratio. Molecular docking studies were carried out against EGFRWT and EGFRT790M.

| S-EPMC9466626 | biostudies-literature

Crystal structure of 4-allyl-sulfanyl-1H-pyrazolo-[3,4-d]pyrimidine.

Project description:In the title compound, C8H8N4S, the pyrazolo-[3,4-d]pyrimidine ring system is essentially planar, with a maximum deviation from the mean plane of 0.025 (3) Å. The allyl group is disordered over two sites in a 0.512 (6):0.488 (6) ratio. In the crystal, mol-ecules are linked by pairs of N-H⋯N hydrogen bonds, forming inversion dimers with an R 2 (2)(8) graph-set motif.

| S-EPMC4186177 | biostudies-literature

Crystal structure of 1-ethyl-pyrazolo[3,4-d]pyrimidine-4(5H)-thione.

Project description:In the title compound, C7H8N4S, the methyl C atom is displaced by 1.232 (7) Å from the mean plane of the pyrazolo-[3,4-d]pyrimidine ring system (r.m.s. deviation = 0.007 Å). The N-N-C-Cm (m = meth-yl) torsion angle is -60.3 (6)°. In the crystal, mol-ecules are linked by N-H⋯S hydrogen bonds, generating [010] chains, which are reinforced by C-H⋯N inter-actions. The chains are cross-linked by weak C-H⋯S hydrogen bonds, generating (001) sheets.

| S-EPMC4186190 | biostudies-literature

Crystal structure of 1-methyl-4-methyl-sulfanyl-1H-pyrazolo-[3,4-d]pyrimidine.

Project description:In the title compound, C7H8N4S, the non-H atoms of the pyrazolo-[3,4-d]pyrimidine ring system and the methyl-sulfanyl group lie on a crystallographic mirror plane. In the crystal, mol-ecules are linked via a number of ?-? inter-actions [centroid-centroid distances vary from 3.452?(7) to 3.6062?(8)?Å], forming a three-dimensional structure.

| S-EPMC4257437 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data