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

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2024-12-22 DOI:10.1021/acs.jmedchem.4c02394

Zhe Nie, Roger Bonnert, Jet Tsien, Xiaoyi Deng, Christopher Higgs, Farah El Mazouni, Xiaoyu Zhang, Renzhe Li, Nhi Ho, Victoria Feher, Janet Paulsen, David M. Shackleford, Kasiram Katneni, Gong Chen, Alice C. F. Ng, Mitchell McInerney, Wen Wang, Jessica Saunders, Daniel Collins, Dandan Yan, Peng Li, Michael Campbell, Rahul Patil, Atanu Ghoshal, Pallab Mondal, Abhijit Kundu, Rajesh Chittimalla, Muralikumar Mahadeva, Sreekanth Kokkonda, John White, Rishi Das, Partha Mukherjee, Iñigo Angulo-Barturen, María Belén Jiménez-Díaz, Robert Malmstrom, Morgan Lawrenz, Agustina Rodriguez-Granillo, Pradipsinh K. Rathod, Diana R. Tomchick, Michael J. Palmer, Benoît Laleu, Tian Qin, Susan A. Charman, Margaret A. Phillips

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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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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.