Pyrimidine-Based Inhibitors of Dynamin I GTPase Activity: Competitive Inhibition at the Pleckstrin Homology Domain
2017 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 60, no 1, 349-361 p.Article in journal (Refereed) Published
The large GTPase dynamin mediates membrane fission during clathrin-mediated endocytosis (CME). The aminopyrimidine compounds, were reported to disrupt clynamin localization to the plasina membrane via the PH domain and,iniplicate this mechanism in the inhibition of CME. We have used a computational approach of binding site identification, docking, and interaction energy calculations to design and synthesize a new library of aminopyrimidine analogues targeting site-2 of the pleckstrin homology (PH) domain. The optimized analogues showed low micromolar inhibition against both dynamin I (IC50 = 10.6 +/- 1.3 to 1.6 +/- 0.3 mu M) and CME (IC50(CME) = 65.9 +/- 7.7 to 17 +/- 1.1 mM), which makes this. series among The more potent inhibitors of dynamin.and CME yet reported. In:CME and growth inhibition cell-based assays, the data obtained Was consistent with dynamin inhibition. CEREP ExpresS profiling identified off-.target effects at the cholecystokinin, dopamine D-2, histamine H-1 and H-2, melanocortin, rnelatonin, muscarir* M-1 and M-3 neurokinin, opioid KOP and serotonin receptors.
Place, publisher, year, edition, pages
2017. Vol. 60, no 1, 349-361 p.
Earth and Related Environmental Sciences
IdentifiersURN: urn:nbn:se:mdh:diva-34881DOI: 10.1021/acs.jmedchem.6b01422ISI: 000392035100023OAI: oai:DiVA.org:mdh-34881DiVA: diva2:1074834