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Structure-based discovery of novel small molecule inhibitors of platelet-derived growth factor-B.
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2019 (English)In: Bioorganic chemistry, ISSN 1090-2120, article id 103374Article in journal (Refereed) Epub ahead of print
Abstract [en]

Platelet-derived growth factor (PDGF) is a family of growth factors with mitogenic and chemotactic activity. However, uncontrolled and overactivated PDGF signaling has been implicated in a variety of diseases, such as cancers and atherosclerosis. In this context, inhibition of PDGF-PDGFR signaling is of paramount importance in progression of such diseases. The purpose of the current study was to identify novel PDGF-B inhibitors using virtual screening methods. To this end, a combination of molecular modeling techniques such as molecular docking and dynamics simulation, as well as drug likeness filtering criteria, was applied to select anti-PDGF peptidomimetic candidates based on crystallography solved structure of an anti-PDGF-B monoclonal antibody named, MOR8457. In vitro biological assays of the selected compounds revealed two of them being active at micromolar IC50 concentrations. The presented work can provide a framework for systematic peptidomimetic identification for anti-PDGF-B agents from large chemical libraries.

Place, publisher, year, edition, pages
2019. article id 103374
Keywords [en]
Anti-PDGF-B agents, MOR8457 antibody, Molecular docking, Molecular dynamics simulation, Platelet-derived growth factor-B, Virtual screening
National Category
Chemical Sciences Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-400211DOI: 10.1016/j.bioorg.2019.103374PubMedID: 31699389OAI: oai:DiVA.org:uu-400211DiVA, id: diva2:1380550
Available from: 2019-12-19 Created: 2019-12-19 Last updated: 2019-12-19

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