Exploring the Activity Profile of TbrPDEB1 and hPDE4 Inhibitors Using Free Energy Perturbation.

ABSTRACT: Human African trypanosomiasis (HAT) is a neglected tropical disease caused by the parasite Trypanosoma brucei (T.b.). A validated target for the treatment of HAT is the parasitic T.b. cyclic nucleotide phosphodiesterase B1 (TbrPDEB1). Although nanomolar TbrPDEB1 inhibitors have been obtained, their activity against the off-target human PDE4 (hPDE4) is likely to lead to undesirable clinical side effects, such as nausea, emesis, and immune suppression. Thus, new and more selective TbrPDEB1 inhibitors are still needed. This retrospective study evaluated the free energy perturbation (FEP+) method to predict the affinity profiles of TbrPDEB1 inhibitors against hPDE4. We demonstrate that FEP+ can be used to accurately predict the activity profiles of these homologous protein

SUBMITTER: Zara L 

PROVIDER: S-EPMC9190044 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature