Structure-Based Discovery and Development of Highly Potent Dihydroorotate Dehydrogenase Inhibitors for Malaria Chemoprevention
Malaria remains a serious global health challenge, yet treatment and control programs are threatened by drug resistance. Dihydroorotate dehydrogenase (DHODH) was clinically validated as a target for treatment and prevention of malaria through human studies with DSM265, but currently no drugs against this target are in clinical use. We used structure-based computational tools including free energy perturbation (FEP+) to discover highly ligand efficient, potent, and selective pyrazole-based <i>Plasmodium</i> DHODH inhibitors through a scaffold hop from a pyrrole-based series. Optimized pyrazole-based compounds were identified with low nM-to-pM <i>Plasmodium falciparum</i> cell potency and oral activity in a humanized SCID mouse malaria infection model. The lead compound DSM1465 is more potent and has improved absorption, distribution, metabolism and excretion/pharmacokinetic (ADME/PK) properties compared to DSM265 that support the potential for once-monthly chemoprevention at a low dose. This compound meets the objective of identifying compounds with potential to be used for monthly chemoprevention in Africa to support malaria elimination efforts.
Authors
- Benoı̂t Laleu (ORCID: https://orcid.org/0000-0002-7530-2113)
- Chris Higgs (ORCID: https://orcid.org/0000-0003-4207-5513)
- Margaret A. Phillips (ORCID: https://orcid.org/0000-0001-5250-5578)
- Rajesh Chittimalla
- Diana R. Tomchick (ORCID: https://orcid.org/0000-0002-7529-4643)
- Agustina Rodriguez-Granillo (ORCID: https://orcid.org/0000-0001-8535-5502)
- Jet Tsien (ORCID: https://orcid.org/0000-0002-2052-8051)
- Victoria A. Feher (ORCID: https://orcid.org/0000-0001-9899-8304)
- Atanu Ghoshal
- Alice C. F. Ng
- Marı́a Belén Jiménez-Dı́az (ORCID: https://orcid.org/0000-0002-1788-4514)
- Íñigo Angulo‐Barturen (ORCID: https://orcid.org/0000-0002-8800-8132)
- Partha Mukherjee
- Pradipsinh K. Rathod (ORCID: https://orcid.org/0000-0001-7394-1360)
- Tian Qin (ORCID: https://orcid.org/0000-0001-7225-3224)
- Kasiram Katneni
- David M. Shackleford (ORCID: https://orcid.org/0000-0002-8229-6591)
- Jessica Saunders
- Renzhe Li (ORCID: https://orcid.org/0009-0006-9775-3587)
- Mitchell P. McInerney (ORCID: https://orcid.org/0009-0001-1411-3650)
- Daniel Collins (ORCID: https://orcid.org/0000-0002-4826-1889)
- Janet L. Paulsen (ORCID: https://orcid.org/0000-0003-3169-356X)
- Morgan Lawrenz (ORCID: https://orcid.org/0000-0002-4798-6423)
- Pallab Mondal
- Roger V. Bonnert (ORCID: https://orcid.org/0000-0002-2976-7374)
- Susan A. Charman (ORCID: https://orcid.org/0000-0003-1753-8213)
- Farah El Mazouni
- Robert D. Malmstrom
- Zhe Nie (ORCID: https://orcid.org/0009-0009-5125-8929)
- Sreekanth Kokkonda
- Rahul Patil (ORCID: https://orcid.org/0000-0003-0530-6933)
- Gong Chen (ORCID: https://orcid.org/0000-0002-5067-9889)
- Xiaoyu Zhang (ORCID: https://orcid.org/0009-0004-3923-651X)
- Peng Li (ORCID: https://orcid.org/0000-0002-7751-1146)
- Wen Wang (ORCID: https://orcid.org/0000-0002-5812-6744)
- Xiaoyi Deng (ORCID: https://orcid.org/0000-0001-8827-4812)
- Michael Palmer (ORCID: https://orcid.org/0000-0002-6037-4421)
- Michael Campbell
- Dandan Yan
- Rishi Das
- Nhi Ho
- Abhijit Kundu
- Muralikumar Mahadeva
- John White (ORCID: https://orcid.org/0000-0001-7895-4443)
Institutions
- University of Washington (US)
- Schrodinger (United States) (US)
- Euskadiko Parke Teknologikoa (ES)
- Syngene International (India) (IN)
- Medicines for Malaria Venture (CH)
- Monash University (AU)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-12-23
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02394
- Citations
- 9
- Primary Topic
- HIV/AIDS drug development and treatment
- Type
- article
- Field-Weighted Citation Impact
- 3.50
Funders
- U.S. Department of Energy
- Bill and Melinda Gates Foundation
- Welch Foundation
- Medicines for Malaria Venture
- National Institutes of Health