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Targeting a hidden site on class A beta-lactamases

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dc.contributor.authorSARIYAR AKBULUT, BERNA
dc.contributor.authorsAvci, Fatma Gizem; Altinisik, Fatma Ece; Karacan, Ipek; Karagoz, Duygu Senturk; Ersahin, Serhat; Eren, Ayse; Sayar, Nihat Alpagu; Ulu, Didem Vardar; Ozkirimli, Elif; Akbulut, Berna Sariyar
dc.date.accessioned2022-03-12T22:26:34Z
dc.date.available2022-03-12T22:26:34Z
dc.date.issued2018
dc.description.abstractIncreasing resistance against available orthosteric beta-lactamase inhibitors necessitates the search for novel and powerful inhibitor molecules. In this respect, allosteric inhibitors serve as attractive alternatives. Here, we examine the structural basis of inhibition in a hidden, druggable pocket in TEM-1 betalactamase. Based on crystallographic evidence that 6-cyclohexyl-1-hexyl-beta-D-maltoside (CYMAL-6) binds to this site, first we determined the kinetic mechanism of inhibition by CYMAL-6. Activity measurements with CYMAL-6 showed that it competitively inhibits the wild type enzyme. Interestingly, it exhibits a steep dose -response curve with an IC50 of 100 mu M. The IC50 value changes neither with different enzyme concentration nor with incubation of the enzyme with the inhibitor, showing that inhibition is not aggregation -based. The presence of the same concentrations of CYMAL-6 does not influence the activity of lactate dehydrogenase, further confirming the specificity of CYMAL-6 for TEM-1 beta-lactamase. Then, we identified compounds with high affinity to this allosteric site by virtual screening using Glide and Schrodinger Suite. Virtual screening performed with 500,000 drug like compounds from the ZINC database showed that top scoring compounds interact with the hydrophobic pocket that forms between H10 and Hll helices and with the catalytically important Arg244 residue through pi -cation interactions. Discovery of novel chemical scaffolds that target this allosteric site will pave the way for a new avenue in the design of new antimicrobials. (C) 2018 Elsevier Inc. All rights reserved.
dc.identifier.doi10.1016/j.jmgm.2018.06.007
dc.identifier.eissn1873-4243
dc.identifier.issn1093-3263
dc.identifier.pubmed29960255
dc.identifier.urihttps://hdl.handle.net/11424/235085
dc.identifier.wosWOS:000444664100016
dc.language.isoeng
dc.publisherELSEVIER SCIENCE INC
dc.relation.ispartofJOURNAL OF MOLECULAR GRAPHICS & MODELLING
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.subjectBeta-lactamase
dc.subjectInhibition
dc.subjectAllostery
dc.subjectCYMAL-6
dc.subjectDocking
dc.subjectVirtual screening
dc.subjectALLOSTERIC SITE
dc.subjectACTIVE-SITE
dc.subjectPROTEIN
dc.subjectINHIBITORS
dc.subjectGENERATION
dc.subjectRESISTANCE
dc.subjectDISCOVERY
dc.subjectDOCKING
dc.subjectGLIDE
dc.titleTargeting a hidden site on class A beta-lactamases
dc.typearticle
dspace.entity.typePublication
local.avesis.iddce76b3a-d42a-45da-a173-577b38792f7b
local.import.packageSS17
local.indexed.atWOS
local.indexed.atSCOPUS
local.indexed.atPUBMED
local.journal.numberofpages9
local.journal.quartileQ2
oaire.citation.endPage133
oaire.citation.startPage125
oaire.citation.titleJOURNAL OF MOLECULAR GRAPHICS & MODELLING
oaire.citation.volume84
relation.isAuthorOfPublicationa9f127d3-8332-44dd-a532-34f3ef20bdb5
relation.isAuthorOfPublication.latestForDiscoverya9f127d3-8332-44dd-a532-34f3ef20bdb5

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