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

Abstract

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 bacteria directly, there is a reduced risk for producing drug-resistant bacteria.. Since human matrix-metalloproteinases (MMPs) have large structural similar in the active sites with PLN, 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, agents inhibiting the activity of only PLN and not MMP are required. 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 than MMPs and be potent antimicrobial agents capable of inhibiting the PLN activity.

Bacterial Zinc Metalloenzyme Inhibitors: Recent Advances and Future Perspectives

“…The binding site is allocated among two helices and their connective loop (Figure 4a). Pseudolysin contains a zinc and a calcium ion [49]. The Ca 2+ is useful for protein stability, whereas the Zn 2+ close to the cleavage site plays a catalytic role [50].…”