{"id":"https://openalex.org/W7143370552","doi":"https://doi.org/10.20944/preprints202603.2227.v1","title":"Computer-Aided Discovery of a \u03b2-Lactam-Independent Deep-Pocket PBP2a Binding Scaffold for Combating MRSA via Pharmacophore-Guided Scaffold Hopping and Bioisosteric Replacement","display_name":"Computer-Aided Discovery of a \u03b2-Lactam-Independent Deep-Pocket PBP2a Binding Scaffold for Combating MRSA via Pharmacophore-Guided Scaffold Hopping and Bioisosteric Replacement","publication_year":2026,"publication_date":"2026-03-27","ids":{"openalex":"https://openalex.org/W7143370552","doi":"https://doi.org/10.20944/preprints202603.2227.v1"},"language":"en","primary_location":{"id":"doi:10.20944/preprints202603.2227.v1","doi":"https://doi.org/10.20944/preprints202603.2227.v1","is_oa":true,"landing_page_url":"https://doi.org/10.20944/preprints202603.2227.v1","pdf_url":null,"source":{"id":"https://openalex.org/S6309402219","display_name":"Preprints.org","issn_l":null,"issn":null,"is_oa":true,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":null,"host_organization_name":null,"host_organization_lineage":["https://openalex.org/P4310310987"],"host_organization_lineage_names":["Multidisciplinary Digital Publishing Institute"],"type":"repository"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"submittedVersion","is_accepted":false,"is_published":false,"raw_source_name":null,"raw_type":"posted-content"},"volume":null,"type":"preprint","is_traditional":true,"indexed_in":["crossref"],"open_access":{"is_oa":true,"oa_status":"green","oa_url":"https://doi.org/10.20944/preprints202603.2227.v1","any_repository_has_fulltext":true},"authorships":[{"author_position":"first","author":{"id":"https://openalex.org/A5131002417","display_name":"Kolala Kapisha","orcid":null,"observed_orcids":[]},"institutions":[],"countries":[],"is_corresponding":false,"raw_author_name":"Kolala Kapisha","raw_affiliation_strings":[],"raw_orcid":null,"affiliations":[]},{"author_position":"last","author":{"id":"https://openalex.org/A5060509997","display_name":"Hanzooma Hatwiko","orcid":"https://orcid.org/0009-0004-5098-907X","observed_orcids":["https://orcid.org/0009-0004-5098-907X"]},"institutions":[],"countries":[],"is_corresponding":false,"raw_author_name":"Hanzooma Hatwiko","raw_affiliation_strings":[],"raw_orcid":null,"affiliations":[]}],"institutions":[],"countries_distinct_count":0,"institutions_distinct_count":0,"corresponding_author_ids":[],"corresponding_institution_ids":[],"apc_list":null,"apc_paid":null,"fwci":null,"has_fulltext":false,"cited_by_count":0,"citation_normalized_percentile":null,"cited_by_percentile_year":null,"biblio":{"volume":null,"issue":null,"first_page":null,"last_page":null},"is_retracted":false,"is_paratext":false,"is_xpac":false,"primary_topic":{"id":"https://openalex.org/T10211","display_name":"Computational Drug Discovery Methods","score":0.9907000064849854,"subfield":{"id":"https://openalex.org/subfields/3002","display_name":"Drug Discovery"},"field":{"id":"https://openalex.org/fields/30","display_name":"Pharmacology, Toxicology and Pharmaceutics"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},"topics":[{"id":"https://openalex.org/T10211","display_name":"Computational Drug Discovery Methods","score":0.9907000064849854,"subfield":{"id":"https://openalex.org/subfields/3002","display_name":"Drug Discovery"},"field":{"id":"https://openalex.org/fields/30","display_name":"Pharmacology, Toxicology and Pharmaceutics"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T10195","display_name":"Antimicrobial Resistance in Staphylococcus","score":0.005400000140070915,"subfield":{"id":"https://openalex.org/subfields/2725","display_name":"Infectious Diseases"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}},{"id":"https://openalex.org/T14099","display_name":"Synthesis and Characterization of Heterocyclic Compounds","score":0.0008999999845400453,"subfield":{"id":"https://openalex.org/subfields/1605","display_name":"Organic Chemistry"},"field":{"id":"https://openalex.org/fields/16","display_name":"Chemistry"},"domain":{"id":"https://openalex.org/domains/3","display_name":"Physical Sciences"}}],"keywords":[{"id":"https://openalex.org/keywords/methicillin-resistant-staphylococcus-aureus","display_name":"methicillin-resistant Staphylococcus aureus","score":0.9549999833106995},{"id":"https://openalex.org/keywords/penicillin-binding-protein-2a","display_name":"penicillin-binding protein 2a","score":0.9679999947547913},{"id":"https://openalex.org/keywords/allosteric-regulation","display_name":"allosteric regulation","score":0.7250000238418579},{"id":"https://openalex.org/keywords/deep-pockets","display_name":"deep pockets","score":0.47699999809265137},{"id":"https://openalex.org/keywords/scaffold-hopping","display_name":"scaffold hopping","score":0.9940000176429749},{"id":"https://openalex.org/keywords/bioisosteric-replacement","display_name":"bioisosteric replacement","score":0.9509999752044678},{"id":"https://openalex.org/keywords/ceftaroline","display_name":"ceftaroline","score":0.9309999942779541},{"id":"https://openalex.org/keywords/transpeptidase","display_name":"transpeptidase","score":0.703000009059906},{"id":"https://openalex.org/keywords/antimicrobial-resistance","display_name":"antimicrobial resistance","score":0.765999972820282},{"id":"https://openalex.org/keywords/computer-aided-drug-design","display_name":"computer-aided drug design","score":0.6840000152587891}],"concepts":[{"id":"https://openalex.org/C56173144","wikidata":"https://www.wikidata.org/wiki/Q1539893","display_name":"Pharmacophore","level":2,"score":0.914900004863739},{"id":"https://openalex.org/C89429830","wikidata":"https://www.wikidata.org/wiki/Q735710","display_name":"Scaffold","level":2,"score":0.7894999980926514},{"id":"https://openalex.org/C41685203","wikidata":"https://www.wikidata.org/wiki/Q1974042","display_name":"Docking (animal)","level":2,"score":0.6592000126838684},{"id":"https://openalex.org/C166342909","wikidata":"https://www.wikidata.org/wiki/Q845326","display_name":"Allosteric regulation","level":3,"score":0.6592000126838684},{"id":"https://openalex.org/C70721500","wikidata":"https://www.wikidata.org/wiki/Q177005","display_name":"Computational biology","level":1,"score":0.6055999994277954},{"id":"https://openalex.org/C185592680","wikidata":"https://www.wikidata.org/wiki/Q2329","display_name":"Chemistry","level":0,"score":0.5807999968528748},{"id":"https://openalex.org/C53105671","wikidata":"https://www.wikidata.org/wiki/Q14777816","display_name":"Rational design","level":2,"score":0.5741999745368958},{"id":"https://openalex.org/C74187038","wikidata":"https://www.wikidata.org/wiki/Q1418791","display_name":"Drug discovery","level":2,"score":0.5239999890327454},{"id":"https://openalex.org/C53645450","wikidata":"https://www.wikidata.org/wiki/Q907093","display_name":"Scaffold protein","level":3,"score":0.4648999869823456},{"id":"https://openalex.org/C103697762","wikidata":"https://www.wikidata.org/wiki/Q4112105","display_name":"Virtual screening","level":3,"score":0.4519999921321869},{"id":"https://openalex.org/C139489369","wikidata":"https://www.wikidata.org/wiki/Q770846","display_name":"Structural similarity","level":2,"score":0.37279999256134033},{"id":"https://openalex.org/C2775905019","wikidata":"https://www.wikidata.org/wiki/Q192572","display_name":"In silico","level":3,"score":0.3603000044822693},{"id":"https://openalex.org/C107824862","wikidata":"https://www.wikidata.org/wiki/Q616005","display_name":"Binding site","level":2,"score":0.3506999909877777},{"id":"https://openalex.org/C11804247","wikidata":"https://www.wikidata.org/wiki/Q896177","display_name":"Protein\u2013protein interaction","level":2,"score":0.33970001339912415},{"id":"https://openalex.org/C177212765","wikidata":"https://www.wikidata.org/wiki/Q627335","display_name":"Workflow","level":2,"score":0.3269999921321869},{"id":"https://openalex.org/C51639874","wikidata":"https://www.wikidata.org/wiki/Q167149","display_name":"Plasma protein binding","level":2,"score":0.3240000009536743},{"id":"https://openalex.org/C21951064","wikidata":"https://www.wikidata.org/wiki/Q899212","display_name":"Combinatorial chemistry","level":1,"score":0.3181999921798706},{"id":"https://openalex.org/C55493867","wikidata":"https://www.wikidata.org/wiki/Q7094","display_name":"Biochemistry","level":1,"score":0.2976999878883362},{"id":"https://openalex.org/C47701112","wikidata":"https://www.wikidata.org/wiki/Q735188","display_name":"Protein structure","level":2,"score":0.2957000136375427},{"id":"https://openalex.org/C193042331","wikidata":"https://www.wikidata.org/wiki/Q1772003","display_name":"Structure\u2013activity relationship","level":3,"score":0.29350000619888306},{"id":"https://openalex.org/C77319485","wikidata":"https://www.wikidata.org/wiki/Q7251520","display_name":"Protein\u2013ligand docking","level":4,"score":0.28519999980926514},{"id":"https://openalex.org/C147816474","wikidata":"https://www.wikidata.org/wiki/Q169525","display_name":"Protein engineering","level":3,"score":0.2833999991416931},{"id":"https://openalex.org/C3019856697","wikidata":"https://www.wikidata.org/wiki/Q912894","display_name":"Competitive binding","level":3,"score":0.28040000796318054},{"id":"https://openalex.org/C2780430158","wikidata":"https://www.wikidata.org/wiki/Q7685902","display_name":"Target protein","level":3,"score":0.2736000120639801},{"id":"https://openalex.org/C63479239","wikidata":"https://www.wikidata.org/wiki/Q7353546","display_name":"Robustness (evolution)","level":3,"score":0.2732999920845032},{"id":"https://openalex.org/C71240020","wikidata":"https://www.wikidata.org/wiki/Q186011","display_name":"Stereochemistry","level":1,"score":0.2720000147819519},{"id":"https://openalex.org/C124790011","wikidata":"https://www.wikidata.org/wiki/Q2069797","display_name":"Peptidomimetic","level":3,"score":0.2696000039577484},{"id":"https://openalex.org/C12554922","wikidata":"https://www.wikidata.org/wiki/Q7100","display_name":"Biophysics","level":1,"score":0.26910001039505005},{"id":"https://openalex.org/C2779489039","wikidata":"https://www.wikidata.org/wiki/Q188121","display_name":"Staphylococcus aureus","level":3,"score":0.26080000400543213},{"id":"https://openalex.org/C64903051","wikidata":"https://www.wikidata.org/wiki/Q2198549","display_name":"Drug development","level":3,"score":0.2572999894618988},{"id":"https://openalex.org/C164126121","wikidata":"https://www.wikidata.org/wiki/Q766383","display_name":"Quantitative structure\u2013activity relationship","level":2,"score":0.257099986076355},{"id":"https://openalex.org/C3020299119","wikidata":"https://www.wikidata.org/wiki/Q423026","display_name":"Binding pocket","level":3,"score":0.25049999356269836}],"mesh":[],"locations_count":1,"locations":[{"id":"doi:10.20944/preprints202603.2227.v1","doi":"https://doi.org/10.20944/preprints202603.2227.v1","is_oa":true,"landing_page_url":"https://doi.org/10.20944/preprints202603.2227.v1","pdf_url":null,"source":{"id":"https://openalex.org/S6309402219","display_name":"Preprints.org","issn_l":null,"issn":null,"is_oa":true,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":null,"host_organization_name":null,"host_organization_lineage":["https://openalex.org/P4310310987"],"host_organization_lineage_names":["Multidisciplinary Digital Publishing Institute"],"type":"repository"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"submittedVersion","is_accepted":false,"is_published":false,"raw_source_name":null,"raw_type":"posted-content"}],"best_oa_location":{"id":"doi:10.20944/preprints202603.2227.v1","doi":"https://doi.org/10.20944/preprints202603.2227.v1","is_oa":true,"landing_page_url":"https://doi.org/10.20944/preprints202603.2227.v1","pdf_url":null,"source":{"id":"https://openalex.org/S6309402219","display_name":"Preprints.org","issn_l":null,"issn":null,"is_oa":true,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":null,"host_organization_name":null,"host_organization_lineage":["https://openalex.org/P4310310987"],"host_organization_lineage_names":["Multidisciplinary Digital Publishing Institute"],"type":"repository"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"submittedVersion","is_accepted":false,"is_published":false,"raw_source_name":null,"raw_type":"posted-content"},"sustainable_development_goals":[{"id":"https://metadata.un.org/sdg/3","score":0.8048999905586243,"display_name":"Good health and well-being"}],"study_designs":[],"awards":[],"funders":[],"has_content":{"grobid_xml":false,"pdf":false},"content_urls":null,"referenced_works_count":0,"referenced_works":[],"related_works":["https://openalex.org/W4410493068","https://openalex.org/W1823576624","https://openalex.org/W3095564395","https://openalex.org/W4388734257","https://openalex.org/W2018970015","https://openalex.org/W4292265067","https://openalex.org/W7223051935","https://openalex.org/W7125383672","https://openalex.org/W3189652744","https://openalex.org/W4407986450"],"abstract_inverted_index":{"Methicillin-resistant":[0],"Staphylococcus":[1],"aureus":[2],"(MRSA)":[3],"remains":[4,57],"a":[5,19,41,63,99,272],"major":[6],"driver":[7],"of":[8,14,27,51,75,115,140,236,263,285],"antimicrobial":[9,291],"resistance":[10],"due":[11],"to":[12,70,149],"expression":[13],"penicillin-binding":[15],"protein":[16],"2a":[17],"(PBP2a),":[18],"transpeptidase":[20],"whose":[21],"conformational":[22,138],"regulation":[23],"limits":[24],"the":[25,122,141,181,187,209,218,230,234,237,265,283],"efficacy":[26],"most":[28,188],"\u03b2-lactam":[29,219,255],"antibiotics.":[30],"Structural":[31],"studies":[32],"have":[33],"shown":[34],"that":[35,45,245],"PBP2a":[36,123,266,279],"activity":[37],"is":[38],"modulated":[39],"through":[40,159],"distal":[42],"regulatory":[43,78,119,210,267],"pocket":[44],"controls":[46],"catalytic-site":[47],"accessibility,":[48],"yet":[49],"exploitation":[50],"this":[52,77],"mechanism":[53],"for":[54,217,276],"inhibitor":[55],"design":[56,67,239],"limited.":[58],"The":[59],"present":[60],"study":[61,270],"applied":[62],"pharmacophore-guided":[64],"computer-aided":[65],"drug":[66],"(CADD)":[68],"strategy":[69,275],"identify":[71,258],"\u03b2-lactam\u2013independent":[72],"scaffolds":[73,261],"capable":[74,262],"engaging":[76,264],"region.":[79],"A":[80],"literature-guided":[81],"workflow":[82],"integrating":[83],"similarity":[84,108],"screening,":[85],"pharmacophore":[86],"modeling,":[87],"scaffold":[88,152,160,247],"hopping,":[89],"and":[90,106,129,137,162,166,193,202,204,229,257,281],"bioisosteric":[91,164],"replacement":[92],"was":[93,96,146],"implemented.":[94],"Ceftaroline":[95],"selected":[97],"as":[98],"reference":[100,220],"ligand":[101],"based":[102],"on":[103],"clinical":[104],"relevance":[105],"structural":[107,251],"analysis.":[109],"Docking":[110],"validation":[111,223],"revealed":[112],"limited":[113],"interaction":[114,144,175,194,206],"ceftaroline":[116],"with":[117,171,200,254],"key":[118],"residues":[120,131],"within":[121,208],"deep":[124],"pocket,":[125],"particularly":[126],"Asp516,":[127],"Tyr519,":[128],"Gln521,":[130],"implicated":[132],"in":[133,177,289],"allosteric":[134],"signal":[135],"propagation":[136],"control":[139],"enzyme.":[142],"Residue-level":[143],"analysis":[145,176],"therefore":[147],"used":[148],"guide":[150],"rational":[151,246],"redesign.":[153],"Three":[154],"novel":[155],"analogues":[156],"were":[157,214],"generated":[158],"hopping":[161],"targeted":[163],"modification":[165],"evaluated":[167],"using":[168],"molecular":[169],"docking":[170],"PyRx":[172],"followed":[173],"by":[174],"Discovery":[178],"Studio.":[179],"Among":[180],"designed":[182],"compounds,":[183],"Analogue":[184],"2":[185],"demonstrated":[186],"favorable":[189],"predicted":[190],"binding":[191],"affinity":[192],"stability,":[195],"establishing":[196],"directional":[197],"hydrogen":[198],"bonding":[199],"Asp516":[201],"Gln521":[203],"improved":[205],"density":[207],"pocket.":[211,268],"These":[212],"interactions":[213],"not":[215],"observed":[216],"ligand.":[221],"Pharmacophore":[222],"confirmed":[224],"alignment":[225],"between":[226],"similarity-derived":[227],"candidates":[228],"redesigned":[231],"scaffolds,":[232],"supporting":[233],"robustness":[235],"computational":[238,274],"framework.":[240],"Collectively,":[241],"these":[242],"findings":[243],"demonstrate":[244],"redesign":[248],"can":[249],"overcome":[250],"limitations":[252],"associated":[253],"antibiotics":[256],"chemically":[259],"distinct":[260],"This":[269],"proposes":[271],"reproducible":[273],"discovering":[277],"non-\u03b2-lactam":[278],"modulators":[280],"highlights":[282],"role":[284],"CADD-driven":[286],"medicinal":[287],"chemistry":[288],"accelerating":[290],"discovery.":[292]},"counts_by_year":[],"updated_date":"2026-11-09T13:22:03.289127","created_date":"2026-03-31T00:00:00"}
