{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T11:42:40Z","timestamp":1753875760832,"version":"3.41.2"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2020,12,14]],"date-time":"2020-12-14T00:00:00Z","timestamp":1607904000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,7,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Billions of people are affected by fungal infection worldwide, which is a major cause of morbidity and mortality in humans. Regardless of development in the field of antifungal therapeutics over the last three decades, multidrug resistance and limited efficacy of available antifungal drugs are very prominent and still a great hurdle in the patient treatment. The current antifungal pipeline is dry, which is needed to be strengthened. Although several strategies have been implemented over time to discover novel promising antifungal leads, but very little emphasis has been given to address the gap of fungal target identification. Undeniably, the need for identifying novel cellular fungal targets is as vital as discovering novel antifungal leads and a structural bioinformatics approach could be an effective strategy in this regard. To address the issue, we have performed in silico screening to identify a few potent multiple targeting ligands and their respective antifungal targets. Thus, we offer a perspective on the phenomena of \u2018target shortage\u2019 and least explored \u2018multiple targeting\u2019 being the most underrated challenges in antifungal drug discovery. \u2018Structural bioinformatics\u2019 could be an effective approach in the recognition of new\/innovative antifungal target and identification\/development of novel antifungal lead molecule aiming multiple molecular targets of the fungal pathogen.<\/jats:p>","DOI":"10.1093\/bib\/bbaa343","type":"journal-article","created":{"date-parts":[[2020,11,11]],"date-time":"2020-11-11T12:09:45Z","timestamp":1605096585000},"source":"Crossref","is-referenced-by-count":9,"title":["Target shortage and less explored multiple targeting: hurdles in the development of novel antifungals but overcome\/addressed effectively through structural bioinformatics"],"prefix":"10.1093","volume":"22","author":[{"given":"Anubhuti","family":"Jha","sequence":"first","affiliation":[{"name":"Department of Biotechnology, National Institute of Technology, Raipur, Chhattisgarh 492010, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Archana","family":"Vimal","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, National Institute of Technology, Raipur, Chhattisgarh 492010, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8735-479X","authenticated-orcid":false,"given":"Awanish","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, National Institute of Technology, Raipur, Chhattisgarh 492010, India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,12,14]]},"reference":[{"key":"2021072117024666100_ref1","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/nrd.2017.46","article-title":"The antifungal pipeline: a reality check","volume":"16","author":"Perfect","year":"2017","journal-title":"Nat Rev Drug Discov"},{"key":"2021072117024666100_ref2","doi-asserted-by":"crossref","DOI":"10.3390\/microorganisms8020154","article-title":"Candida albicans antifungal resistance and tolerance in bloodstream infections: the triad yeast-host-antifungal","volume":"8","author":"Costa-de-Oliveira","year":"2020","journal-title":"Microorganisms"},{"key":"2021072117024666100_ref3","doi-asserted-by":"crossref","DOI":"10.3390\/antibiotics9040150","article-title":"Prevalence and therapeutic challenges of fungal drug resistance: role for plants in drug discovery","volume":"9","author":"Marquez","year":"2020","journal-title":"Antibiotics"},{"issue":"36","key":"2021072117024666100_ref4","article-title":"Antifungal therapy: new advances in the understanding and treatment of mycosis","volume":"8","author":"Scorzoni","year":"2017","journal-title":"Front Microbiol"},{"key":"2021072117024666100_ref5","doi-asserted-by":"crossref","DOI":"10.3390\/antibiotics9060312","article-title":"Candidiasis and mechanisms of antifungal resistance","volume":"9","author":"Bhattacharya","year":"2020","journal-title":"Antibiotics"},{"key":"2021072117024666100_ref6","doi-asserted-by":"crossref","DOI":"10.3390\/metabo10030106","article-title":"Antifungal drugs","volume":"10","author":"Hou\u0161\u0165","year":"2020","journal-title":"Metabolites"},{"key":"2021072117024666100_ref7","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.colsurfb.2016.03.013","article-title":"Time to overcome fluconazole resistant Candida isolates: solid lipid nanoparticles as a novel antifungal drug delivery system","volume":"142","author":"Moazeni","year":"2016","journal-title":"Colloids Surf B Biointerfaces"},{"key":"2021072117024666100_ref8","first-page":"1172","article-title":"Advances in computational approaches in identifying synergistic drug combinations","volume":"19","author":"Sheng","year":"2018","journal-title":"Brief Bioinform"},{"key":"2021072117024666100_ref9","first-page":"467","article-title":"Novel in silico tools for designing peptide-based subunit vaccines and immunotherapeutics","volume":"18","author":"Dhanda","year":"2017","journal-title":"Brief Bioinform"},{"key":"2021072117024666100_ref10","article-title":"In silico prediction of host\u2013pathogen protein interactions in melioidosis pathogen Burkholderia pseudomallei and human reveals novel virulence factors and their targets","volume":"23","author":"Loaiza","year":"2020","journal-title":"Brief Bioinform"},{"key":"2021072117024666100_ref11","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.tips.2010.07.003","article-title":"Evolutionary inspirations for drug discovery","volume":"31","author":"Zhang","year":"2010","journal-title":"Trends Pharmacol Sci"},{"key":"2021072117024666100_ref12","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1517\/17460441.2.6.799","article-title":"How to design multi-target drugs: target search options in cellular networks","volume":"2","author":"Korcsm\u00e1ros","year":"2007","journal-title":"Expert Opin Drug Discov"},{"key":"2021072117024666100_ref13","doi-asserted-by":"crossref","first-page":"52","DOI":"10.3923\/tb.2015.52.62","article-title":"Identification of putative therapeutic targets in Candida tropicalis: an in silico approach","volume":"8","author":"Ravinarayanan","year":"2015","journal-title":"Trends Bioinform"},{"key":"2021072117024666100_ref14","doi-asserted-by":"crossref","first-page":"D455","DOI":"10.1093\/nar\/gkn858","article-title":"DEG 5.0, a database of essential genes in both prokaryotes and eukaryotes","volume":"37","author":"Zhang","year":"2009","journal-title":"Nucleic Acids Res"},{"key":"2021072117024666100_ref15","doi-asserted-by":"crossref","DOI":"10.2174\/15701808113109990054","article-title":"Improvement of virtual screening predictions using computational intelligence methods","author":"Cano","year":"2013"},{"key":"2021072117024666100_ref16","doi-asserted-by":"crossref","DOI":"10.1016\/j.imu.2020.100385","article-title":"Subtractive genomics approach towards the identification of novel therapeutic targets against human Bartonella bacilliformis","volume":"20","author":"Khan","year":"2020","journal-title":"Informatics Med Unlocked"},{"key":"2021072117024666100_ref17","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1038\/nchembio.1199","article-title":"Biology and drug discovery","volume":"9","author":"Schenone","year":"2017","journal-title":"Nat Chem Biol"},{"key":"2021072117024666100_ref18","doi-asserted-by":"crossref","first-page":"D447","DOI":"10.1093\/nar\/gku1003","article-title":"STRING v10: protein-protein interaction networks, integrated over the tree of life","volume":"43","author":"Szklarczyk","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"2021072117024666100_ref19","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.jmgm.2013.01.010","article-title":"Pharmacophore modeling , virtual screening , docking and in silico ADMET analysis of protein kinase B ( PKB \u03b2) inhibitors","volume":"42","author":"Vyas","year":"2013","journal-title":"J Mol Graph Model"},{"key":"2021072117024666100_ref20","first-page":"102","article-title":"Phenotypic screening: a more rapid route to target deconvolution","volume":"13","author":"Harrison","year":"2014","journal-title":"Nat Rev Drug Discov"},{"key":"2021072117024666100_ref21","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.ymeth.2014.09.006","article-title":"Tools for in silico target fishing","volume":"71","author":"Cereto-Massagu\u00e9","year":"2015","journal-title":"Methods"},{"key":"2021072117024666100_ref22","doi-asserted-by":"crossref","first-page":"2554","DOI":"10.1016\/j.jprot.2011.05.011","article-title":"From in silico target prediction to multi-target drug design: current databases, methods and applications","volume":"74","author":"Koutsoukas","year":"2011","journal-title":"J Proteomics"},{"key":"2021072117024666100_ref23","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1080\/21505594.2016.1196300","article-title":"Combinatorial strategies for combating invasive fungal infections","volume":"8","author":"Spitzer","year":"2017","journal-title":"Virulence"},{"key":"2021072117024666100_ref24","doi-asserted-by":"crossref","DOI":"10.3390\/molecules191219292","article-title":"Natural cinnamic acids, synthetic derivatives and hybrids with antimicrobial activity","volume":"19","author":"Guzman","year":"2014","journal-title":"Molecules"},{"key":"2021072117024666100_ref25","doi-asserted-by":"crossref","first-page":"2955","DOI":"10.4155\/fmc-2018-0479","article-title":"Anticandidal agent for multiple targets: the next paradigm in the discovery of proficient therapeutics\/overcoming drug resistance","volume":"11","author":"Jha","year":"2019","journal-title":"Future Med Chem"},{"volume-title":"J Fungi (Basel)","key":"2021072117024666100_ref26"},{"key":"2021072117024666100_ref27","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.00662","article-title":"The evolution of drug resistance in clinical isolates of Candida albicans","volume":"4","author":"Ford","year":"2015","journal-title":"Elife"},{"key":"2021072117024666100_ref28","doi-asserted-by":"crossref","first-page":"202","DOI":"10.3389\/fphar.2014.00202","article-title":"Efflux pump proteins in antifungal resistance","volume":"5","author":"Prasad","year":"2014","journal-title":"Front Pharmacol"},{"key":"2021072117024666100_ref29","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1186\/1471-2164-9-579","article-title":"MFS transportome of the human pathogenic yeast Candida albicans","volume":"9","author":"Gaur","year":"2008","journal-title":"BMC Genomics"},{"key":"2021072117024666100_ref30","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1128\/EC.5.2.347-358.2006","article-title":"The Cek1 and Hog1 mitogen-activated protein kinases play complementary roles in cell wall biogenesis and chlamydospore formation in the fungal pathogen Candida albicans","volume":"5","author":"Eisman","year":"2006","journal-title":"Eukaryot Cell"},{"key":"2021072117024666100_ref31","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1003696","article-title":"Activation of the Cph1-dependent MAP kinase signaling pathway induces white-opaque switching in Candida albicans","volume":"9","author":"Ram\u00edrez-Zavala","year":"2013","journal-title":"PLoS Pathog"},{"key":"2021072117024666100_ref32","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1111\/j.1567-1364.2010.00626.x","article-title":"The MAP kinase-activated protein kinase Rck2p regulates cellular responses to cell wall stresses, filamentation and virulence in the human fungal pathogen Candida albicans","volume":"10","author":"Li","year":"2010","journal-title":"FEMS Yeast Res"},{"key":"2021072117024666100_ref33","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1003305","article-title":"Genetic control of conventional and pheromone-stimulated biofilm formation in Candida albicans","volume":"9","author":"Lin","year":"2013","journal-title":"PLoS Pathog"},{"key":"2021072117024666100_ref34","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1007\/s00203-015-1146-8","article-title":"ERG11 mutations and expression of resistance genes in fluconazole-resistant Candida albicans isolates","volume":"197","author":"Xu","year":"2015","journal-title":"Arch Microbiol"},{"key":"2021072117024666100_ref35","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1093\/jac\/dki112","article-title":"Squalene epoxidase encoded by ERG1 affects morphogenesis and drug susceptibilities of Candida albicans","volume":"55","author":"Pasrija","year":"2005","journal-title":"J Antimicrob Chemother"},{"key":"2021072117024666100_ref36","volume-title":"Anticandidal Agents","author":"Kumar","year":"2016","edition":"1st"},{"key":"2021072117024666100_ref37","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s11046-010-9342-1","article-title":"Molecular mechanisms of resistance to 5-fluorocytosine in laboratory mutants of Candida glabrata","volume":"171","author":"Vandeputte","year":"2011","journal-title":"Mycopathologia"}],"container-title":["Briefings in Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/bib\/article-pdf\/22\/4\/bbaa343\/39139500\/bbaa343.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/bib\/article-pdf\/22\/4\/bbaa343\/39139500\/bbaa343.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,21]],"date-time":"2021-07-21T17:22:34Z","timestamp":1626888154000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bib\/article\/doi\/10.1093\/bib\/bbaa343\/6032617"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,14]]},"references-count":37,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2021,7,20]]}},"URL":"https:\/\/doi.org\/10.1093\/bib\/bbaa343","relation":{},"ISSN":["1467-5463","1477-4054"],"issn-type":[{"type":"print","value":"1467-5463"},{"type":"electronic","value":"1477-4054"}],"subject":[],"published-other":{"date-parts":[[2021,7]]},"published":{"date-parts":[[2020,12,14]]},"article-number":"bbaa343"}}