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

Author(s)

Froes, Thamires Quadros ^[1] ; Campisano Zapata, Luana Carlos ^[1] ; Akamine, Juliana Sayuri ^[1] ; Castilho, Marcelo Santos ^[2] ; Nonato, Maria Cristina ^[1]

Affiliation

^[1] Fac Ciencias Farmaceut Ribeirao Preto USP, Lab Cristalog Proteinas, Av Cafe S-N, BR-14040900 Ribeirao Preto, SP - Brazil

^[2] Univ Fed Bahia, Fac Farm, Av Barao Jeremoabo S-N Ondina, BR-40170115 Salvador, BA - Brazil

• Document type: Review article
• Source: CURRENT TOPICS IN MEDICINAL CHEMISTRY; v. 21, n. 23, p. 2134-2154, 2021.
• Web of Science Citations: 0

Abstract

Background: Dihydroorotate dehydrogenase (DHODH) has long been recognized as an important drug target for proliferative and parasitic diseases, including compounds that exhibit try-panocidal 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 ex-ploited to predict DHODH hot spots. Moreover, it provides for the first time a review of the antivi-ral 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 inHsDHODH is correlated with the ligand effi-ciency (LE) of its known inhibitors, and Fragment Hotspot Maps pointed out the contribution of se-lected moieties to the overall LE. The conformational flexibility of the active site loop TcDHODH was found to have a major impact on the druggability of the orotate binding site. In ad-dition, both FTMap and Fragment Hotspot Maps servers predict a novel pocket inTcDHODH 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. (AU)

• FAPESP's process: 19/08376-6 - Structural characterization of the enzyme dihydroorotate dehydrogenase of Schistosoma mansoni
• Grantee: Luana Carlos Campisano Zapata
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 20/06190-0 - Drug repurposing and search of selective inhibitors for human dihydroorotate dehydrogenase as a strategy in fighting against COVID-19
• Grantee: Maria Cristina Nonato
• Support Opportunities: Regular Research Grants