title: Designing the angiogenic inhibitor for brain tumor via disruption of VEGF and IL17A expression.
abstract: Glioblastoma multiforme is a highly malignant, heterogenic, and drug resistant tumor. The blood-brain barrier (BBB), systemic cytotoxicity, and limited specificity are the main obstacles in designing brain tumor drugs. In this study a computational approach was used to design brain tumor drugs that could downregulate VEGF and IL17A in glioblastoma multiforme type four. Computational screening tools were used to evaluate potential candidates for antiangiogenic activity, target binding, BBB permeability, and ADME physicochemical properties. Additionally, in vitro cytotoxicity, migration, invasion, tube formation, apoptosis, ROS and ELISA assays were conducted for molecule 6 that was deemed most likely to succeed. The efflux ratio of membrane permeability and calculated docking scores of permeability to glycoproteins (P-gps) were used to determine the BBB permeability of the molecules. The results showed BBB permeation for molecule 6, with the predicted efficiency of 0.55kcal/mol and binding affinity of -37kj/mol corresponding to an experimental efflux ratio of 0.625 and predicted -15kj/mol of binding affinity for P-gps. Molecule 6 significantly affected the angiogenesis pathways by 2-fold downregulation of IL17A and VEGF through inactivation of active sites of HSP90 (predicted binding: -37kj/mol, predicted efficiency: 0.55kcal/mol) and p23 (predicted binding: 12kj/mol, predicted efficiency: 0.17kcal/mol) chaperon proteins. Additionally, molecule 6 activated the 17.38% relative fold of ROS level at 18.3μg/mL and upregulated the caspase which lead the potential synergistic apoptosis through the antiangiogenic activity of molecule 6 and thereby the highly efficacious anticancer upshot. The results indicate that the binding of the molecules to the therapeutic target is not essential to produce a lethal effect on cancer cells of the brain and that antiangiogenic efficiency is much more important.
authors.affiliation: EMAN Cancer Research Laboratory, Department of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden, Pulau Pinang, Malaysia. Electronic address: jupitex@gmail.com.
authors.forename: Md Shamsuddin Sultan
authors.initials: MS
authors.lastname: Khan
authors.affiliation: EMAN Cancer Research Laboratory, Department of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden, Pulau Pinang, Malaysia. Electronic address: aminmalikshah@gmail.com.
authors.forename: Amin Malik Shah Abdul
authors.initials: AM
authors.lastname: Majid
authors.affiliation: The School of Chemical Sciences, Universiti Sains Malaysia (USM), 11800 Penang, Malaysia.
authors.forename: Muhammad Adnan
authors.initials: MA
authors.lastname: Iqbal
authors.affiliation: EMAN Cancer Research Laboratory, Department of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden, Pulau Pinang, Malaysia; QUEST International University, Ipoh, Perak, Malaysia.
authors.forename: Aman Shah Abdul
authors.initials: AS
authors.lastname: Majid
authors.affiliation: EMAN Cancer Research Laboratory, Department of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden, Pulau Pinang, Malaysia.
authors.forename: Majed
authors.initials: M
authors.lastname: Al-Mansoub
authors.affiliation: The School of Chemical Sciences, Universiti Sains Malaysia (USM), 11800 Penang, Malaysia.
authors.forename: Rosenani S M Anwarul
authors.initials: RS
authors.lastname: Haque
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001812:Blood-Brain Barrier / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D020381:Interleukin-17 / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D062105:Molecular Docking Simulation; D021281:Quantitative Structure-Activity Relationship; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D007093:Imidazoles; D020381:Interleukin-17; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D020169:Caspases
keywords: Blood–brain-barrier; Glioblastoma; IL17A; P-gp; VEGF