Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series

Author:

Palmer Michael J.1,Deng Xiaoyi2,Watts Shawn3,Krilov Goran3,Gerasyuto Aleksey3,Kokkonda Sreekanth4,El Mazouni Farah2,White John4,White Karen L.5,Striepen Josefine6,Bath Jade6,Schindler Kyra A.6,Yeo Tomas6,Shackleford David M.5,Mok Sachel6ORCID,Deni Ioanna6,Lawong Aloysus2,Huang Ann2,Chen Gong5,Wang Wen5,Jayaseelan Jaya5,Katneni Kasiram5,Patil Rahul5,Saunders Jessica5,Shahi Shatrughan P.7,Chittimalla Rajesh7,Angulo-Barturen Iñigo8,Jiménez-Díaz María Belén8,Wittlin Sergio910,Tumwebaze Patrick K.11,Rosenthal Philip J.12,Cooper Roland A.13,Aguiar Anna Caroline Campos14,Guido Rafael V. C.14,Pereira Dhelio B.15,Mittal Nimisha16,Winzeler Elizabeth A.16ORCID,Tomchick Diana R.2,Laleu Benoît1,Burrows Jeremy N.1ORCID,Rathod Pradipsinh K.4,Fidock David A.617,Charman Susan A.5,Phillips Margaret A.2ORCID

Affiliation:

1. Medicines for Malaria Venture, 1215 Geneva, Switzerland

2. Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, Texas 75390-9135, United States

3. Schrodinger, Inc., 120 West 45th St, 17th Floor, New York, New York 100036-4041, United States

4. Departments of Chemistry and Global Health, University of Washington, Seattle, Washington 98195, United States

5. Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia

6. Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, New York 10032, United States

7. Syngene International Ltd, Bangalore 560099, India

8. TAD, Biscay Science and Technology Park, Astondo Bidea, BIC Bizkaia Bd 612, Derio, 48160 Bizkaia, Basque Country, Spain

9. Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland

10. University of Basel, 4002 Basel, Switzerland

11. Infectious Diseases Research Collaboration, Kampala, Uganda

12. Department of Medicine, University of California, San Francisco, California 94143, United States

13. Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, California 94901, United States

14. University of Sao Paulo, Sao Carlos Institute of Physics, Sáo Carlos, SP 13560-970, Brazil

15. Tropical Medicine Research Center of Rondonia, Av. Guaporé, 215, Porto Velho, RO 76812-329, Brazil

16. Department of Pediatrics, Division of Host-Microbe Systems and Therapeutics, School of Medicine, University of California San Diego, La Jolla, California 92093, United States

17. Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York 10032, United States

Funder

Welch Foundation

National Institute of Allergy and Infectious Diseases

University of Texas Southwestern Medical Center

Bill and Melinda Gates Foundation

Medicines for Malaria Venture

U.S. Department of Defense

Publisher

American Chemical Society (ACS)

Subject

Drug Discovery,Molecular Medicine

Reference75 articles.

1. Malaria

2. World Health Organization. World Malaria Report. https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2020 (accessed Dec 15, 2020).

3. Malaria

4. Antimalarial Drug Resistance: A Threat to Malaria Elimination

5. Artemisinin Action and Resistance in Plasmodium falciparum

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