title: Dynamic Structure and Inhibition of a Malaria Drug Target: Geranylgeranyl Diphosphate Synthase.
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.
authors: Department of Pharmacology and Department of Chemistry & Biochemistry, University of California at San Diego , La Jolla, California 92093, United States.|Howard Hughes Medical Institute, University of California at San Diego , La Jolla, California 92093, United States.|National Biomedical Computation Resource, University of California at San Diego , La Jolla, California 92093, United States.
authors: Clarisse
authors: C
authors: G Ricci
authors: Department of Chemistry, University of Illinois at Urbana-Champaign , 600 South Mathews Avenue, Urbana, Illinois 61801, United States.
authors: Yi-Liang
authors: YL
authors: Liu
authors: Department of Chemistry, University of Illinois at Urbana-Champaign , 600 South Mathews Avenue, Urbana, Illinois 61801, United States.
authors: Yonghui
authors: Y
authors: Zhang
authors: Department of Chemistry, University of Illinois at Urbana-Champaign , 600 South Mathews Avenue, Urbana, Illinois 61801, United States.
authors: Yang
authors: Y
authors: Wang
authors: Department of Chemistry, University of Illinois at Urbana-Champaign , 600 South Mathews Avenue, Urbana, Illinois 61801, United States.
authors: Wei
authors: W
authors: Zhu
authors: Department of Chemistry, University of Illinois at Urbana-Champaign , 600 South Mathews Avenue, Urbana, Illinois 61801, United States.
authors: Eric
authors: E
authors: Oldfield
authors: Department of Pharmacology and Department of Chemistry & Biochemistry, University of California at San Diego , La Jolla, California 92093, United States.|Howard Hughes Medical Institute, University of California at San Diego , La Jolla, California 92093, United States.|National Biomedical Computation Resource, University of California at San Diego , La Jolla, California 92093, United States.
authors: J Andrew
authors: JA
authors: McCammon
mesh_terms: D000962:Antimalarials / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D010966:Plasmodium vivax / Q000187:drug effects*; D025341:Principal Component Analysis; D013816:Thermodynamics
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase