Solving the riddle: Unraveling the mechanisms of blocking the binding of leukotoxin by therapeutic antagonists in periodontal diseases

Abstract Aggregatibacter actinomycetemcomitans is a Gram‐negative bacteria that has gained wide recognition for its causative role in the development of various immune diseases, which includes localized aggressive periodontitis. 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‐expressed leukocyte function–associated receptor (LFA‐1) in its active state. Therapeutic compounds that interfere with this pathogenic process and abrogate A. actinomycetemcomitans 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‐1 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‐1 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‐exposed 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 A. actinomycetemcomitans diseases.