DHODH Hot Spots: An Underexplored Source to Guide Drug Development Efforts

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.

Cite this article as:

Froes Quadros Thamires, Zapata Carlos Campisano Luana , Akamine Sayuri Juliana , Castilho Santos Marcelo *, Nonato Cristina Maria *, DHODH Hot Spots: An Underexplored Source to Guide Drug Development Efforts, Current Topics in Medicinal Chemistry 2021; 21 (23) . https://dx.doi.org/10.2174/1568026621666210804122320