LogP

• Drugability is the balance of the ability to bind with a target and the ability to move in physiological matrix
• Drugs need to be lipid soluble enough to pass through lipid membranes but water soluble enough to dissolve in the gut for absorption
• Drugs need to possess multiple simultaneous properties:

  • Potency
  • Solubility
  • Absorption
  • Specificity
  • Metabolic stability
  • Safety
• Lipinski Rule of 5 outlines a set of 5 drug-like characteristics identified in most approved drugs
• Lipinski Rule of Five:

  1. Molecular weight
  2. Lipophilicity (LogP)
  3. Hydrogen bond donors
  4. Hydrogen bond acceptors
• TPSA is an overall measure of the number of atoms functioning as H bond acceptors or donors
• Only the desolvated form of a non-ionised drug can permeate membranes
• Desolvated = water-free
• P is the partition coefficient
• [compound] in organic solvent is taken in octanol
• Octanol is a flexible molecule that takes various shapes, with both hydrophobic and hydrophilic ends
• octanol imitates a lipid membrane
• [compound] in aqueous solvent is taken in water
• Negative logP values implies that the drug has an affinity for the aqueous phase
• LogP = 0 means that equal concentrations of the drug are distributed in both the organic and aqueous phase
• Positive LogP values mean that more of the compound is in the organic phase
• LogP predicts movement in membranes
• Greater LogP implies that the compound will move easily through membranes
• LogP predicts:

  • Potency
  • Selectivity
  • Compound solubility
  • Membrane permeability
  • Metabolism
• Promiscuity increases with lipophilicity
• Promiscuity = interacts with more proteins
• Promiscuity decreases with molecular weight
• Lipophilicity is linked to plasma protein binding, CYP and transporter interactions
• Pharma companies tend to add lipophilic molecules to lead compounds to increase their in vitro activity
• Adding lipophilic molecules to lead compounds results in:

  • Decreased absorption, as it cannot be dissolved in water
  • Binding to unwanted targets
  • Reactive metabolites
• LE gives the relative free-binding energy in kcal/mol per each non-hydrogen atom (N)
• LE = ligand efficiency
• Large pIC50 value means that the drug has high potency
• LLE relates IC50 to lipophilicity by putting a logP penalty on the molecule
• LLE takes loss of bioavailability as LogP increases into account
• LLE = lipophilic ligand efficiency
• LELP is the price of ligand efficiency paid in LogP
• LELP is more strict and therefore better at identifying lead compounds with chance for success
• Pan Assay Interference Compounds = PAINs
• LELP = ligand efficiency lipophilic price
• LogP may not be the only reason for finding a drug to have high promiscuity
• Pan-assay interference compounds can engage in non-specific interactions, causing incorrect reporting that the drug is acting on the target
• Pan-assay interference compounds can be produced many ways:

  • Florescence
  • Strong coloured molecule
  • Metals
  • Other chemical reactions mimicking assay signal
• Redox cyclers produce hydrogen peroxide that can inactivate certain proteins, making the drug look like an antagonist/inhibitor
• High throughput screening can deal with thousands of molecules, therefore necessitating the determination of many LogP values