Wednesday, April 8, 2009

Rule of attraction

The role of fluorine in Ligand – Protein interaction has been well studied, but much less known about the non-bonding interaction of chlorine and bromine with protein.
A new paper (Angew. Chem. Int. Ed 2009, 48, 2911) from Matter demonstrates the non-covalent interaction between the chlorine or bromine and the aromatic ring in protein.

This Cl/Br…pi interaction might be general use in structure based design towards interaction for aromatic amino acids. It is clear that systematic halogen scan (F, Cl and Br) in the lead structure will be a useful strategy for the lead optimization, not only block the metabolic labile position but also to strengthen protein-ligand binding interaction.

Friday, April 3, 2009

Fluorine in Drug Development

The Drug development process (fig. 2) is a lengthy, high risk and costly endeavor; many strategies exist to accelerate the target to clinical candidate selection as well as to provide the highest quality of the candidate.

Fluorine and its isotope have many role in the different phases of drug development process. The number of fluorine containing drugs are growing rapidly which include the best selling drugs such as Atorvastatin, Prozac, Ciprobay and Pantoprazole (fig.1).

Target Identification

PET is a nuclear medicine imaging tool which allows three- dimentional quantitative determination of the distribution of radioactive whin the human body.The relatively long half life, high % of β emmision and relatively low positron energy maks 18 F makes it is most favourabe for the Positron emission tomography (PET) Studies.
F MR allows detection of the presence of the target, in vivo, includeing assessment of the presence of targets, as well as quantification of their spatial and temporal distribution.

(fig. 2)

F MR - Fluorine Magnetic Resonance.
PET- Positron emission tomography.

Lead Finding

Once the target is chosen and identified, the next stage is typically high-throughput screening of large libraries of chemicals for their ability to modulate the target. F M R allows compound screening using cell based and animal based assays (whereas HTS restricted to cell based assays).
Fluorine plays an important role in the physicochemical properties (see lead optimization) of the molecule so the HTS screening of Fluorine containing libraries will help for the lead finding.

Lead Optimization

The small and highly electronegative fluorine atom can play a role in medicinal chemistry. Systematic Fluorine scan of ligands is a promising strategy in lead optimization. it not only helps to enhance the physicochemical properties but also to strengthen Protein –Ligand binding interaction. This would make the molecule a safer candidate.
The current strategies for introducing fluorine atoms in to molecules are centred to
1. Improve metabolic stability.
2. Alter physicochemical properties such as pKa and lipophilicity, dipole moment and even the chemical reactivity and stability of the neighboring functional groups.
3. Enhance the binding efficacy and selectivity in pharmaceuticals.
4. Bioisosterism.

Preclinical and Clinical Studies

The suboptimal pharmacokinetics and pharmacodynamic can lead up to 40% of the drug candidate failing to make it to phase 1 trial. PET can allow assessment of parameters such as drug absorption biodistribution, metabolism, delivery and dose uses in preclinical studies and can help in systematic planning latter phases.

The estimation of pharmacological agents to reache its targets is important in drugs trials. This can be done by the ADME techniques based on blood or tissue harvesting and subsequent drug and metabolite analysis. This approach is less than a prefect because plasma levels of compound often do not reflect concentrations in specific tissue, because of the presence of physicochemical barriers such as between blood and brain.
Proton Emission tomography provide the reliable measure of tissue drug concentration.


1) Muller. K et al, Science. 317, 2007, 1881.
2) Reid G. D et al, Drug discovery today. 13, 2008, 473.
3) Willmann J. K. et al, Nature reviews drug discovery. 7, 2008, 591.