{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T00:35:25Z","timestamp":1792715725317,"version":"4.5.0"},"reference-count":61,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,3]],"date-time":"2025-08-03T00:00:00Z","timestamp":1754179200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Antibacterial resistance (ABR) poses a major challenge to global health, with methicillin-resistant Staphylococcus aureus (MRSA) being one of the prominent multidrug-resistant strains. MRSA has developed resistance through the expression of Penicillin-Binding Protein 2a (PBP2a), a key transpeptidase enzyme involved in bacterial cell wall biosynthesis. Objectives: The objective was to design and characterize a novel small-molecule inhibitor targeting PBP2a as a strategy to combat MRSA. Methods: We synthesized a new indole triazole conjugate (ITC) using eco-friendly and click chemistry approaches. In vitro antibacterial tests were performed against a panel of strains to evaluate the ITC antibacterial potential. Further, a series of in silico evaluations like molecular docking, MD simulations, free energy landscape (FEL), and principal component analysis (PCA) using the crystal structure of PBP2a (PDB ID: 4CJN), in order to predict the mechanism of action, binding mode, structural stability, and energetic profile of the 4CJN-ITC complex. Results: The compound ITC exhibited noteworthy antibacterial activity, which effectively inhibited the selected strains. Binding score and energy calculations demonstrated high affinity of ITC for the allosteric site of PBP2a and significant interactions responsible for complex stability during MD simulations. Further, FEL and PCA provided insights into the conformational behavior of ITC. These results gave the structural clues for the inhibitory action of ITC on the PBP2a. Conclusions: The integrated in vitro and in silico studies corroborate the potential of ITC as a promising developmental lead targeting PBP2a in MRSA. This study demonstrates the potential usage of rational drug design approaches in addressing therapeutic needs related to ABR.<\/jats:p>","DOI":"10.3390\/pharmaceutics17081013","type":"journal-article","created":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T09:41:17Z","timestamp":1754300477000},"page":"1013","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Synthesis and Antibacterial Evaluation of an Indole Triazole Conjugate with In Silico Evidence of Allosteric Binding to Penicillin-Binding Protein 2a"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8298-1161","authenticated-orcid":false,"given":"Vidyasrilekha","family":"Sanapalli","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, The Nilgiris 643001, TN, India"},{"name":"Department of Pharmaceutical Chemistry, School of Pharmacy & Technology Management, SVKM\u2019s Narsee Monjee Institute of Management Studies (NMIMS) Deemed-to-be-University, Jadcherla, Hyderabad 509301, TS, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9162-5553","authenticated-orcid":false,"given":"Bharat Kumar Reddy","family":"Sanapalli","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, The Nilgiris 643001 TN, India"},{"name":"Department of Pharmacology, School of Pharmacy & Technology Management, SVKM\u2019s Narsee Monjee Institute of Management Studies (NMIMS) Deemed-to-be-University, Jadcherla, Hyderabad 509301, TS, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9770-9371","authenticated-orcid":false,"given":"Afzal Azam","family":"Mohammed","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, The Nilgiris 643001, TN, India"},{"name":"Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Technical Education, Noida 201301, UP, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Michael, C.A., Dominey-Howes, D., and Labbate, M. 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