Note: How Big Is Too Big for Cell Permeability?

Note: How Big Is Too Big for Cell Permeability?
Doi: 10.1021/acs.jmedchem.7b00237

Prediction from human proteome to have protein-protein interactions; 100,000 - 1,000,000 (PPI)

Challenges for PPI (nonclassical drug targets)

• Large
• Featureless (no unique characteristic)
• Flexible interfaces
• Mostly, located inside the cells

Biologics drug;

• Lack of cell permeability
• Low bioavailability on oral administration

In chemical side -- it is really important to understand the chemical space of peptides which contain following properties

• Cell permeable
• Drug-like molecules

This paper mentioned “cyclic peptide” chemical space.

What Cameron Pye did;

• Evaluate the impact of molecular size + lipophilicity on membrane permeability

To check membrane permeability;

• Using artificial membrane permeability assay (PAMPA)
• MDCK (Madin-Darby canine kidney) cell clone (expresses low levels of P-glycoprotein -- efflux transporter)

**This size-dependent permeability is not compatible with the traditional solubility − diffusion based theories for cell permeability.

Biophysical properties of cyclic peptides need to be done (matching the relationship between cellular diffusion + lipophilicity of cyclic peptides).

PSA -- polar surface area
Cyclosporin A, which can adopt both membrane permeable (low PSA) and water-soluble (high PSA) conformations.

Efflux vs size

cellular efflux that increased with molecular size was observed for macrocyclic compounds in the 400−800 Da size range.

Solute carrier (SLC) superfamilies

• Example: transport of larger HCV NS3/4A protease inhibitors by members of the organic anion transporting polypeptides (OATP/SLCO) family

Transcellular permeability coefficients reported for nanodelivery systems12 are lower than those observed by Pye et al. at MW of ∼1000 Da.


Huge Challenge:
Scope and limitations of drug discovery beyond the rule of 5


Just taking a quick look at solubility screening