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Continuous evaluation and reporting of newer molecular targets and their inhibitors are necessary. Here, we present <jats:sc>l<\/jats:sc>\u2010asparaginase of <jats:italic>N. gonorrhoeae<\/jats:italic> (NgA) as a new molecular target based on structure\u2010based high\u2010throughput screening, molecular dynamics(MD) simulations, and validation by biophysical, biochemical, and cell viability assays. We observed that the NgA is evolutionarily conserved in both the drug\u2010resistant and susceptible strains of <jats:italic>N. gonorrhoeae<\/jats:italic>, indicating its importance in the growth and survival of the pathogen. Three Food and Drug Administration\u2010approved drugs, pemirolast, thalidomide, and decitabine, were identified as potential inhibitors of NgA using high\u2010throughput screening. The binding energies of the drugs with NgA were \u221220.14, \u221219.67, and \u221216.47\u2009kcal\/mol, respectively, compared to \u22126.82\u2009\u00b1\u20091.46 for enzyme\u2013substrate \n<jats:sc>l<\/jats:sc>\u2010Asn, as obtained through MD simulations. Subsequently, fluorescence quenching and differential scanning calorimetry\u00a0experiments validated the in\u00a0silico data. The observance of inhibition of NgA activity at micromolar drug concentrations further strengthened our findings. Conclusive evidence came from the cell viability assays where these drugs were found to impede the growth of <jats:italic>N. gonorrhoeae<\/jats:italic> culture effectively. Thus, our study establishes <jats:sc>l<\/jats:sc>\u2010asparaginase as a new molecular target against gonococcal infections. From this study, we propose that targeting of NgA can be explored to control <jats:italic>N. gonorrhoeae<\/jats:italic> infections in combination therapy.<\/jats:p>","DOI":"10.1002\/jcb.30271","type":"journal-article","created":{"date-parts":[[2022,5,9]],"date-time":"2022-05-09T05:19:32Z","timestamp":1652073572000},"page":"1171-1182","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Antimicrobial\u2010resistant <i>Neisseria gonorrhoeae<\/i> can be targeted using inhibitors against evolutionary conserved<scp>l<\/scp>\u2010asparaginase"],"prefix":"10.1002","volume":"123","author":[{"given":"Shubham","family":"Vashishtha","sequence":"first","affiliation":[{"name":"Kusuma School of Biological Sciences Indian Institute of Technology Delhi  Delhi India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasdeep","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and 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