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

Clarisse G. Ricci, Yi Liang Liu, Yonghui Zhang, Yang Wang, Wei Zhu, Eric Oldfield, J. Andrew McCammon

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)5180-5190
Number of pages11
Issue number36
StatePublished - Sep 13 2016

ASJC Scopus subject areas

  • Biochemistry


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