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