Title:DHODH Hot Spots: An Underexplored Source to Guide Drug Development Efforts
Volume: 21
Issue: 23
Author(s): Thamires Quadros Froes, Luana Carlos Campisano Zapata, Juliana Sayuri Akamine, Marcelo Santos Castilho*Maria Cristina Nonato*
Affiliation:
- Faculdade de Farmacia da Universidade Federal da Bahia, Av. Barao de Jeremoabo s/n Ondina, Salvador-BA, 40170-115,Brazil
- Laboratorio de Cristalografia de Proteinas, Faculdade de Ciencias Farmaceuticas de Ribeirao Preto - USP, Av. do Cafe, s/n - Vila Monte Alegre, Ribeirao Preto-SP, 14040-900,Brazil
Keywords:
DHODH, Hot spots, Antiviral drug, Antitrypanosomal drug, FTMap, Fragment Hotspot Map.
Abstract:
Background: Dihydroorotate dehydrogenase (DHODH) has long been recognized as an
important drug target for proliferative and parasitic diseases, including compounds that exhibit trypanocidal
action and broad-spectrum antiviral activity. Despite numerous and successful efforts in
structural and functional characterization of DHODHs, as well as in the development of inhibitors,
DHODH hot spots remain largely unmapped and underexplored.
Objective: This review describes the tools that are currently available for the identification and
characterization of hot spots in protein structures and how freely available webservers can be exploited
to predict DHODH hot spots. Moreover, it provides for the first time a review of the antiviral
properties of DHODH inhibitors.
Methods: X-ray structures from human (HsDHODH) and Trypanosoma cruzi DHODH
(TcDHODH) had their hot spots predicted by both FTMap and Fragment Hotspot Maps web
servers.
Results: FTMap showed that hot spot occupancy in HsDHODH is correlated with the ligand efficiency
(LE) of its known inhibitors, and Fragment Hotspot Maps pointed out the contribution of selected
moieties to the overall LE. The conformational flexibility of the active site loop in
TcDHODH was found to have a major impact on the druggability of the orotate binding site. In addition,
both FTMap and Fragment Hotspot Maps servers predict a novel pocket in TcDHODH
dimer interface (S6 site).
Conclusion: This review reports how hot spots can be exploited during hit-to-lead steps, docking
studies or even to improve inhibitor binding profile and by doing so using DHODH as a model,
points to new drug development opportunities.
