6ND2

Staphylococcus aureus Dihydrofolate Reductase complexed with NADPH and 6-ETHYL-5-[(3R)-3-[2-METHOXY-5-(PYRIDIN-4-YL)PHENYL]BUT-1-YN-1-YL]PYRIMIDINE-2,4-DIAMINE (UCP1063)

Summary for 6ND2

• Entry DOI: 10.2210/pdb6nd2/pdb
• Descriptor: Dihydrofolate reductase, GLYCEROL, 6-ethyl-5-{(3S)-3-[2-methoxy-5-(pyridin-4-yl)phenyl]but-1-yn-1-yl}pyrimidine-2,4-diamine, ... (5 entities in total)
• Functional Keywords: dhfr, propargyl-linked antifolates, antibiotics, antifolates, oxidoreductase
• Biological source: Staphylococcus aureus
• Total number of polymer chains: 1
• Total formula weight: 19226.52

Authors

Reeve, S.M.,Wright, D.L. (deposition date: 2018-12-13, release date: 2019-09-25, Last modification date: 2023-10-11)

Primary citation

Lombardo, M.N.,G-Dayanandan, N.,Keshipeddy, S.,Zhou, W.,Si, D.,Reeve, S.M.,Alverson, J.,Barney, P.,Walker, L.,Hoody, J.,Priestley, N.D.,Obach, R.S.,Wright, D.L.
Structure-Guided In Vitro to In Vivo Pharmacokinetic Optimization of Propargyl-Linked Antifolates.
Drug Metab.Dispos., 47:995-1003, 2019

PubMed Abstract: Pharmacokinetic/pharmacodynamic properties are strongly correlated with the in vivo efficacy of antibiotics. Propargyl-linked antifolates, a novel class of antibiotics, demonstrate potent antibacterial activity against both Gram-positive and Gram-negative pathogenic bacteria, including multidrug-resistant Here, we report our efforts to optimize the pharmacokinetic profile of this class to best match the established pharmacodynamic properties. High-resolution crystal structures were used in combination with in vitro pharmacokinetic models to design compounds that not only are metabolically stable in vivo but also retain potent antibacterial activity. The initial lead compound was prone to both -oxidation and demethylation, which resulted in an abbreviated in vivo half-life (∼20 minutes) in mice. Stability of leads toward mouse liver microsomes was primarily used to guide medicinal chemistry efforts so robust efficacy could be demonstrated in a mouse disease model. Structure-based drug design guided mitigation of -oxide formation through substitutions of sterically demanding groups adjacent to the pyridyl nitrogen. Additionally, deuterium and fluorine substitutions were evaluated for their effect on the rate of oxidative demethylation. The resulting compound was characterized and demonstrated to have a low projected clearance in humans with limited potential for drug-drug interactions as predicted by cytochrome P450 inhibition as well as an in vivo exposure profile that optimizes the potential for bactericidal activity, highlighting how structural data, merged with substitutions to introduce metabolic stability, are a powerful approach to drug design.

PubMed: 31201212
DOI: 10.1124/dmd.119.086504

Experimental method

X-RAY DIFFRACTION (2.243 Å)