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Biochemistry. 2016 Sep 13;55(36):5180-90. doi: 10.1021/acs.biochem.6b00398. Epub 2016 Sep 1.

Dynamic Structure and Inhibition of a Malaria Drug Target: Geranylgeranyl Diphosphate Synthase.

Author information

1
Department of Pharmacology and Department of Chemistry & Biochemistry, University of California at San Diego , La Jolla, California 92093, United States.
2
Howard Hughes Medical Institute, University of California at San Diego , La Jolla, California 92093, United States.
3
National Biomedical Computation Resource, University of California at San Diego , La Jolla, California 92093, United States.
4
Department of Chemistry, University of Illinois at Urbana-Champaign , 600 South Mathews Avenue, Urbana, Illinois 61801, United States.

Abstract

We report a molecular dynamics investigation of the structure, function, and inhibition of geranylgeranyl diphosphate synthase (GGPPS), a potential drug target, from the malaria parasite Plasmodium vivax. We discovered several GGPPS inhibitors, benzoic acids, and determined their structures crystallographically. We then used molecular dynamics simulations to investigate the dynamics of three such inhibitors and two bisphosphonate inhibitors, zoledronate and a lipophilic analogue of zoledronate, as well as the enzyme's product, GGPP. We were able to identify the main motions that govern substrate binding and product release as well as the molecular features required for GGPPS inhibition by both classes of inhibitor. The results are of broad general interest because they represent the first detailed investigation of the mechanism of action, and inhibition, of an important antimalarial drug target, geranylgeranyl diphosphate synthase, and may help guide the development of other, novel inhibitors as new drug leads.

PMID:
27564465
PMCID:
PMC5319852
DOI:
10.1021/acs.biochem.6b00398
[Indexed for MEDLINE]
Free PMC Article

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