Structure-guided design and biosynthesis of a novel FR-900098 analogue as a potent Plasmodium falciparum 1-deoxy-<scp>d</scp>-xylulose-5-phosphate reductoisomerase (Dxr) inhibitor

Cobb, Ryan E.; Bae, Byungchan; Li, Zhi; DeSieno, Matthew A.; Nair, Satish K.; Zhao, Huimin

doi:10.1039/c4cc09181g

Cited by 10 publications

(6 citation statements)

References 21 publications

(32 reference statements)

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“…FrbF is highly specific for acetyl-CoA (k cat = 1.1 min −1 , K M = 20 μM), but low activity is also observed toward propionyl-CoA, n-butyryl-CoA, malonyl-CoA, and acetoacetyl-CoA. 404,405 Despite the 15-fold smaller k cat /K M value toward propionyl-CoA (k cat = 0.09 min −1 , K M = 24 μM), this promiscuous activity was a sufficient starting point to biosynthesize the N-propionyl analog of 12a in E. coli. 405 This new compound, called FR900098P, is a significantly stronger inhibitor of the target enzyme DXP reductoisomerase (K I = 0.92 nM) than the parent compound 12a (K I = 3.7 nM) and thus points the way to developing more potent antimalarial drugs.…”

Section: Chemical Reviewsmentioning

confidence: 99%

Phosphonate Biochemistry

2016

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Organophosphonic acids are unique as natural products in terms of stability and mimicry. The C-P bond that defines these compounds resists hydrolytic cleavage, while the phosphonyl group is a versatile mimic of transition-states, intermediates, and primary metabolites. This versatility may explain why a variety of organisms have extensively explored the use organophosphonic acids as bioactive secondary metabolites. Several of these compounds, such as fosfomycin and bialaphos, figure prominently in human health and agriculture. The enzyme reactions that create these molecules are an interesting mix of chemistry that has been adopted from primary metabolism as well as those with no chemical precedent. Additionally, the phosphonate moiety represents a source of inorganic phosphate to microorganisms that live in environments that lack this nutrient; thus, unusual enzyme reactions have also evolved to cleave the C-P bond. This review is a comprehensive summary of the occurrence and function of organophosphonic acids natural products along with the mechanisms of the enzymes that synthesize and catabolize these molecules.

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Section: Chemical Reviewsmentioning

confidence: 99%

Phosphonate Biochemistry

2016

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“…Thus, these molecules were more active than fosmidomycin, the reference in the field of DXR inhibition 67 ( Figure 3 ). Recently, structure-guided design 68 and virtual screening 69 were successfully applied in order to identify and evaluate new molecules with a potent inhibitory effect on P. falciparum .…”

Section: Modeling Ligand–protein Interactions In Drug Designmentioning

confidence: 99%

Molecular docking as a popular tool in drug design, an in silico travel

Ruyck¹,

Brysbaert²,

Blossey³

et al. 2016

AABC

220

121

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New molecular modeling approaches, driven by rapidly improving computational platforms, have allowed many success stories for the use of computer-assisted drug design in the discovery of new mechanism-or structure-based drugs. In this overview, we highlight three aspects of the use of molecular docking. First, we discuss the combination of molecular and quantum mechanics to investigate an unusual enzymatic mechanism of a flavoprotein. Second, we present recent advances in anti-infectious agents’ synthesis driven by structural insights. At the end, we focus on larger biological complexes made by protein–protein interactions and discuss their relevance in drug design. This review provides information on how these large systems, even in the presence of the solvent, can be investigated with the outlook of drug discovery.

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“…It was effective in killing P. falciparum at single-digit nanomolar conc., stable in mouse serum but toxic in vivo at 20 mg kg À1 and caused a decrease in parasite load in mouse model of malaria. Considering toxicity issues pertaining to this, related compound KB16 (156) which was designed to target Trypanosoma cruzi and known to have low toxicity in mice, showed signicant decrease of parasitemia at a dose level of 20 mg kg À1 per day upto day 14. This compound targets berghepains (BP1) with IC 50 value of 0.5 mM suggesting that the decrease in parasitemia was due to a combined effect of BP1 and DPAP1 inhibition.…”

Section: Parasite Invasion and Releasementioning

confidence: 99%