Identification of Pak1 inhibitors using water thermodynamic analysis
| العنوان: | Identification of Pak1 inhibitors using water thermodynamic analysis |
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| المؤلفون: | Prajisha Jayaprakash, Saritha Poopandi, Raghu Rangasamy, Ganesh Venkatraman, Jayashree Biswal, Jeyakanthan Jeyaraman, Rayala Suresh Kumar |
| المصدر: | Journal of Biomolecular Structure and Dynamics. 38:13-31 |
| بيانات النشر: | Informa UK Limited, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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. |
| تدمد: | 1538-0254 0739-1102 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::757f275b14c46fd2bf38c4425cdd3fe8Test https://doi.org/10.1080/07391102.2019.1567393Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....757f275b14c46fd2bf38c4425cdd3fe8 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15380254 07391102 |
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