Design of galardine analogs as putative psudolysin inhibitors based on ab initio fragment molecular orbital calculations

Pseudolysin (PLN) is a metalloproteinase secreted from bacteria that degrades extracellular proteins to produce bacterial nutrition. It is thus expected that inhibitors against PLN can suppress the growth of bacteria and their pandemic spread. In addition, since these inhibitors do not attack to bacteria directly, there is a reduced risk for producing drug-resistant bacteria. On the other hand, as PLN has large structural similarity in the active sites with human matrix-metalloproteinases (MMPs), there is a possibility that the inhibitors for PLN also inhibit MMP activity, resulting in a loss of necessary nutrients to be produced by MMPs. Therefore, it is required the agents inhibiting the activity of only PLN not MMPs. In the present study, we employed a hydroxamate compound galardin, which has a significant inhibition effect against PLN and MMP, and investigated its specific interactions with PLN/MMP at atomic and electronic levels, by use of ab initio molecular simulations. Based on the results, we proposed several derivatives of galardin and elucidated which derivatives that can bind more strongly to PLN and be putative antimicrobial agents capable of inhibiting the PLN activity. Communicated by Ramaswamy H. Sarma