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Computational Approaches for the Design of Novel Anticancer Compounds Based on Pyrazolo[3,4-d]pyrimidine Derivatives as TRAP1 Inhibitor
- Source :
- Molecules, Volume 26, Issue 19, Molecules, Vol 26, Iss 5932, p 5932 (2021)
- Publication Year :
- 2021
- Publisher :
- MDPI, 2021.
-
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
- Subjects :
- Quantitative structure–activity relationship
Loo
Stereochemistry
Protein Data Bank (RCSB PDB)
Pharmaceutical Science
Quantitative Structure-Activity Relationship
Antineoplastic Agents
Pyrazole
Molecular Dynamics Simulation
Ligands
Article
Analytical Chemistry
TRAP1
chemistry.chemical_compound
QD241-441
Neoplasms
Drug Discovery
Humans
Computer Simulation
HSP90 Heat-Shock Proteins
Physical and Theoretical Chemistry
ADME
3D-QSAR pharmacophore modeling
Virtual screening
Chemistry
Organic Chemistry
molecular dynamics simulations
virtual screening
Molecular Docking Simulation
TRAP1 kinase
Pyrimidines
Chemistry (miscellaneous)
Docking (molecular)
Molecular Medicine
Pharmacophore
Subjects
Details
- Language :
- English
- ISSN :
- 14203049
- Volume :
- 26
- Issue :
- 19
- Database :
- OpenAIRE
- Journal :
- Molecules
- Accession number :
- edsair.doi.dedup.....6e7c073a530602173d5a437bbf7069d4