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Identification of Pak1 inhibitors using water thermodynamic analysis
- Source :
- Journal of Biomolecular Structure and Dynamics. 38:13-31
- Publication Year :
- 2019
- Publisher :
- Informa UK Limited, 2019.
-
Abstract
- p21-activated kinases (Paks) play an integral component in various cellular diverse processes. The full activation of Pak is dependent upon several serine residues present in the N-terminal region, a threonine present at the activation loop, and finally the phosphorylation of these residues ensure the complete activation of Pak1. The present study deals with the identification of novel potent candidates of Pak1 using computational methods as anti-cancer compounds. A diverse energy based pharmacophore (e-pharmacophore) was developed using four co-crystal inhibitors of Pak1 having pharmacophore features of 5 (DRDRR), 6 (DRHADR), and 7 (RRARDRP and DRRDADH) hypotheses. These models were used for rigorous screening against e-molecule database. The obtained hits were filtered using ADME/T and molecular docking to identify the high affinity binders. These hits were subjected to hierarchical clustering using dendritic fingerprint inorder to identify structurally diverse molecules. The diverse hits were scored against generated water maps to obtain WM/MM ΔG binding energy. Furthermore, molecular dynamics simulation and density functional theory calculations were performed on the final hits to understand the stability of the complexes. Five structurally diverse novel Pak1 inhibitors (4835785, 32198676, 32407813, 76038049, and 32945545) were obtained from virtual screening, water thermodynamics and WM/MM ΔG binding energy. All hits revealed similar mode of binding pattern with the hinge region residues replacing the unstable water molecules in the binding site. The obtained novel hits could be used as a platform to design potent drugs that could be experimentally tested against cancer patients having increased Pak1 expression.
- Subjects :
- 030303 biophysics
Binding energy
Drug Evaluation, Preclinical
Quantitative Structure-Activity Relationship
Computational biology
Molecular Dynamics Simulation
Ligands
Serine
03 medical and health sciences
Molecular dynamics
Structural Biology
Molecule
Binding site
Protein Kinase Inhibitors
Molecular Biology
ADME
0303 health sciences
Virtual screening
Binding Sites
Molecular Structure
Chemistry
Reproducibility of Results
Water
Hydrogen Bonding
General Medicine
Molecular Docking Simulation
p21-Activated Kinases
Drug Design
Thermodynamics
Pharmacophore
Protein Binding
Subjects
Details
- ISSN :
- 15380254 and 07391102
- Volume :
- 38
- Database :
- OpenAIRE
- Journal :
- Journal of Biomolecular Structure and Dynamics
- Accession number :
- edsair.doi.dedup.....757f275b14c46fd2bf38c4425cdd3fe8