2. Academic Validation
  3. Structure-Based Discovery and Development of Highly Potent Dihydroorotate Dehydrogenase Inhibitors for Malaria Chemoprevention

Structure-Based Discovery and Development of Highly Potent Dihydroorotate Dehydrogenase Inhibitors for Malaria Chemoprevention

  • J Med Chem. 2025 Jan 9;68(1):590-637. doi: 10.1021/acs.jmedchem.4c02394.
Zhe Nie 1,  Roger Bonnert 2,  Jet Tsien 3,  Xiaoyi Deng 3,  Christopher Higgs 1,  Farah El Mazouni 3,  Xiaoyu Zhang 3,  Renzhe Li 3,  Nhi Ho 3,  Victoria Feher 1,  Janet Paulsen 1,  David M Shackleford 4,  Kasiram Katneni 4,  Gong Chen 4,  Alice C F Ng 4,  Mitchell McInerney 4,  Wen Wang 4,  Jessica Saunders 4,  Daniel Collins 4,  Dandan Yan 4,  Peng Li 4,  Michael Campbell 4,  Rahul Patil 4,  Atanu Ghoshal 5,  Pallab Mondal 5,  Abhijit Kundu 5,  Rajesh Chittimalla 6,  Muralikumar Mahadeva 6,  Sreekanth Kokkonda 7,  John White 7,  Rishi Das 5,  Partha Mukherjee 5,  Iñigo Angulo-Barturen 8,  María Belén Jiménez-Díaz 8,  Robert Malmstrom 1,  Morgan Lawrenz 1,  Agustina Rodriguez-Granillo 1,  Pradipsinh K Rathod 7,  Diana R Tomchick 9,  Michael J Palmer 2,  Benoît Laleu 2,  Tian Qin 3,  Susan A Charman 4,  Margaret A Phillips 3
Affiliations

Affiliations

  • 1 Schrödinger Inc., 1540 Broadway, New York, New York 10036, United States.
  • 2 MMV Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, 1215 Geneva, Switzerland.
  • 3 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.
  • 4 Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
  • 5 TCGLS, Block BN, Plot 7, Salt Lake Electronics Complex, Sector V, Kolkata 700091, West Bengal, India.
  • 6 Syngene Scientific Solutions Limited, KSP 9000 Campus, Plot No. 7, Neovantage, Synergy Square 2, Kolthur Village, Shameerpet Mandal, Medchal Malkajgiri District, Hyderabad 500 078, Telangana, India.
  • 7 Department of Chemistry, University of Washington, Seattle, Washington 98195, United States.
  • 8 The Art of Discovery, Biscay Science and Technology Park, Astondo Bidea, BIC Bizkaia Bd 612, Derio, 48160 Bizkaia, Basque Country, Spain.
  • 9 Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.
PMID: 39710971 DOI: 10.1021/acs.jmedchem.4c02394
Abstract

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 Plasmodium DHODH inhibitors through a scaffold hop from a pyrrole-based series. Optimized pyrazole-based compounds were identified with low nM-to-pM Plasmodium falciparum 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.

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