Computational analysis of tyrosine phosphatase inhibitor selectivity for the virulence factors YopH and SptP

Bacterial pathogens such as Yersinia and Salmonella represent an important medical concern, causing human diseases ranging from gastrointestinal disease to the plague. The development of novel treatments of these bacterial infections has gained high priority recently due to the emergence of antibiotic resistance in these pathogens and the threat of the use of microbial agents as biological weapons. YopH of Yersinia and SptP of Salmonella are virulence factors that belong to the family of protein tyrosine phosphatases (PTPs). A great challenge remains in the design of selective PTPs inhibitors due to their highly conserved active site. In this paper, we present a comparative docking study to probe the selective inhibition of YopH and SptP with PTP1B in order to better understand their binding interactions with the bacterial tyrosine phosphates. Characterized binding sites in PTP1B were compared with YopH and SptP. Molecular dynamics simulations were used to incorporate ligand-induced conformational changes in the binding sites. These results, together with those binding modes and binding affinities distinguished in individual PTPs, provide insight into the structure-based design of inhibitors for YopH and SptP.