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dc.contributor.authorWeako, Jackson
dc.contributor.authorUba, Abdullahi Ibrahim
dc.contributor.authorKeskin, Özlem
dc.contributor.authorGürsoy, Attila
dc.contributor.authorYelekçi, Kemal
dc.description.abstractMethionine Aminopeptidases MetAPs are divalent-cofactor dependent enzymes that are responsible for the cleavage of the initiator Methionine from the nascent polypeptides. MetAPs are classified into two isoforms: namely, MetAP1 and MetAP2. Several studies have revealed that MetAP2 is upregulated in various cancers, and its inhibition has shown to suppress abnormal or excessive blood vessel formation and tumor growth in model organisms. Clinical studies show that the natural product fumagillin, and its analogs are potential inhibitors of MetAP2. However, due to their poor pharmacokinetic properties and neurotoxicities in clinical studies, their further developments have received a great setback. Here, we apply structure-based virtual screening and molecular dynamics methods to identify a new class of potential inhibitors for MetAP2. We screened Otava's Chemical Library, which consists of about 3 200 000 tangible-chemical compounds, and meticulously selected the top 10 of these compounds based on their inhibitory potentials against MetAP2. The top hit compounds subjected to ADMET predictor using 3 independent ADMET prediction programs, were found to be drug-like. To examine the stability of ligand binding mode, and efficacy, the unbound form of MetAP2, its complexes with fumagillin, spiroepoxytriazole, and the best promising compounds compound-3369841 and compound-3368818 were submitted to 100 ns molecular dynamics simulation. Like fumagillin, spiroepoxytriazole, and both compound-3369841 and compound-3368818 showed stable binding mode over time during the simulations. Taken together, these uninherited-fumagillin compounds may serve as new class of inhibitors or provide scaffolds for further optimization towards the design of more potent MetAP2 inhibitors -development of such inhibitors would be essential strategy against various cancer types.en_US
dc.subjectMetAP2 inhibitorsen_US
dc.subjectStructure-based virtual screeningen_US
dc.subjectMolecular dockingen_US
dc.subjectMolecular dynamics simulationen_US
dc.titleIdentification of potential inhibitors of human methionine aminopeptidase (type II) for cancer therapy: Structure-based virtual screening, ADMET prediction and molecular dynamics studiesen_US
dc.relation.journalComputational Biology and Chemistryen_US
dc.departmentFakülteler, Mühendislik ve Doğa Bilimleri Fakültesi, Biyoinformatik ve Genetik Bölümüen_US
dc.institutionauthorWeako, Jacksonen_US
dc.institutionauthorUba, Abdullahi Ibrahimen_US
dc.institutionauthorYelekçi, Kemalen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US

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