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Its ability to evade host defense mechanisms is mediated by the secretion of leukotoxin (LtxA), which induces death of white blood cells (leukocytes) by specific binding to their surface\u2010expressed leukocyte function\u2013associated receptor (LFA\u20101) in its active state. Therapeutic compounds that interfere with this pathogenic process and abrogate <jats:italic>A. actinomycetemcomitans<\/jats:italic> virulence have been reported in literature. These include doxycycline, and more recently phytochemical compounds such as hamamelitanin, resveratrol, naringin, and quercetin. However, the question remains how do they work? Therefore, with the aid of computational tools, we explore the molecular mechanisms by which they possibly elicit their therapeutic functions. Molecular mechanics Poisson\/Boltzmann surface area analyses revealed that these compounds bind favorably to active LFA\u20101 with high affinity and considerable stability, indicative of their ability to occupy the LtxA binding site (LBS) and prevent LtxA binding. The conformational transition of open LFA\u20101 to its closed state further describe the mechanistic activity of these compounds. In addition to notable reductions in structural mobility and flexibility, the burial of surface\u2010exposed interactive side chains at the LBS was observed, an occurrence that could alter the complementary binding of LtxA. It is also important to mention that these occurrences were induced more prominently by the phytochemicals. We believe that these findings will enhance the scope of drug design and discovery for potent LtxA antagonists with improved activities and therapeutic efficacies in the treatment of virulent <jats:italic>A. actinomycetemcomitans<\/jats:italic> diseases.<\/jats:p>","DOI":"10.1002\/jcb.27254","type":"journal-article","created":{"date-parts":[[2018,8,22]],"date-time":"2018-08-22T15:23:49Z","timestamp":1534951429000},"page":"9364-9379","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Solving the riddle: Unraveling the mechanisms of blocking the binding of leukotoxin by therapeutic antagonists in periodontal diseases"],"prefix":"10.1002","volume":"119","author":[{"given":"Maryam","family":"Abdullahi","sequence":"first","affiliation":[{"name":"Molecular Bio\u2010Computation and Drug Design Laboratory, School of Health Sciences University of KwaZulu\u2010Natal  Durban South 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