Nie Zhe, Bonnert Roger, Tsien Jet, Deng Xiaoyi, Higgs Christopher, El Mazouni Farah, Zhang Xiaoyu, Li Renzhe, Ho Nhi, Feher Victoria, Paulsen Janet, Shackleford David M, Katneni Kasiram, Chen Gong, Ng Alice C F, McInerney Mitchell, Wang Wen, Saunders Jessica, Collins Daniel, Yan Dandan, Li Peng, Campbell Michael, Patil Rahul, Ghoshal Atanu, Mondal Pallab, Kundu Abhijit, Chittimalla Rajesh, Mahadeva Muralikumar, Kokkonda Sreekanth, White John, Das Rishi, Mukherjee Partha, Angulo-Barturen Iñigo, Jiménez-Díaz María Belén, Malmstrom Robert, Lawrenz Morgan, Rodriguez-Granillo Agustina, Rathod Pradipsinh K, Tomchick Diana R, Palmer Michael J, Laleu Benoît, Qin Tian, Charman Susan A, Phillips Margaret A
Schrödinger Inc., 1540 Broadway, New York, New York 10036, United States.
MMV Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, 1215 Geneva, Switzerland.
J Med Chem. 2025 Jan 9;68(1):590-637. doi: 10.1021/acs.jmedchem.4c02394. Epub 2024 Dec 22.
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 DHODH inhibitors through a scaffold hop from a pyrrole-based series. Optimized pyrazole-based compounds were identified with low nM-to-pM 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.
疟疾仍然是一项严峻的全球卫生挑战，然而治疗和控制计划正受到耐药性的威胁。二氢乳清酸脱氢酶（DHODH）已通过使用DSM265的人体研究在临床上被验证为治疗和预防疟疾的靶点，但目前尚无针对该靶点的药物用于临床。我们使用了包括自由能微扰（FEP+）在内的基于结构的计算工具，通过从基于吡咯的系列进行骨架跃迁，发现了高效、强效且具有选择性的基于吡唑的DHODH抑制剂。在人源化SCID小鼠疟疾感染模型中，确定了优化后的基于吡唑的化合物具有低纳摩尔至皮摩尔级别的细胞活性和口服活性。与DSM265相比，先导化合物DSM1465具有更强的效力，并具有改善的吸收、分布、代谢和排泄/药代动力学（ADME/PK）特性，这支持了其在低剂量下每月进行一次化学预防的潜力。该化合物符合鉴定有潜力用于非洲每月化学预防以支持疟疾消除工作的化合物这一目标。
