Ligand-based computational modelling of platelet-derived growth factor beta receptor leading to new angiogenesis inhibitory leads

Rua'a A Al-Aqtash; Malek A Zihlif; Hana Hammad; Zeyad D Nassar; Jehad Al Meliti; Mutasem O Taha

doi:10.1016/j.compbiolchem.2017.10.003

Ligand-based computational modelling of platelet-derived growth factor beta receptor leading to new angiogenesis inhibitory leads

Comput Biol Chem. 2017 Dec:71:170-179. doi: 10.1016/j.compbiolchem.2017.10.003. Epub 2017 Oct 10.

Authors

Rua'a A Al-Aqtash¹, Malek A Zihlif¹, Hana Hammad², Zeyad D Nassar³, Jehad Al Meliti⁴, Mutasem O Taha⁵

Affiliations

¹ Department of Pharmacology, Faculty of Medicine, University of Jordan, Amman, Jordan.
² Department of Biology, University of Jordan, Amman, Jordan.
³ School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
⁴ South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
⁵ Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Jordan, Amman, Jordan. Electronic address: mutasem@ju.edu.jo.

PMID: 29101826
DOI: 10.1016/j.compbiolchem.2017.10.003

Abstract

Platelet derived growth factor beta receptor (PDGFR- β) plays an important role in angiogenesis. PDGFR-β expression is correlated with increased vascularity and maturation of blood vessels in cancer. Pharmacophore modeling and quantitative structure-activity relationship (QSAR) analysis were combined to explore the structural requirements for ligand-PDGFR-β recognition using 107 known PDGFR-β inhibitors. Genetic function algorithm (GFA) coupled to k nearest neighbor (kNN) and multiple linear regression (MLR) analysis were employed to generate predictive QSAR models based on optimal combinations of pharmacophores and physicochemical descriptors. The successful pharmacophores were complemented with exclusion spheres to optimize their receiver operating characteristic curve (ROC) profiles. The QSAR models and their associated pharmacophore hypotheses were validated by identification and experimental evaluation of new angiogenesis inhibitory leads retrieved from the National Cancer Institute (NCI) structural database. Two hits illustrated low micromolar IC₅₀ values in two distinct anti-angiogenesis bioassays.

Keywords: Angiogenesis; PANC-1; PDGFR-β; Pharmacophore; QSAR; Virtual screening.

MeSH terms

Algorithms*
Angiogenesis Inhibitors / chemistry
Angiogenesis Inhibitors / pharmacology*
Humans
Ligands
Linear Models
Models, Molecular
Neovascularization, Pathologic / drug therapy*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Quantitative Structure-Activity Relationship*
Receptor, Platelet-Derived Growth Factor beta / antagonists & inhibitors*
Receptor, Platelet-Derived Growth Factor beta / metabolism

Substances

Angiogenesis Inhibitors
Ligands
Protein Kinase Inhibitors
Receptor, Platelet-Derived Growth Factor beta