properties, metrics, & parameters used to evaluate leads

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Around 2000 compounds have been approved as drugs, and people have studied these compounds intensively to identify trends in what kinds of molecules become drugs. Many insights have been gained by examining physicochemical properties of molecules. For example, Lipinski’s rules are based upon four different physicochemical properties - molecular weight, hydrogen bond donors and acceptors, and log P, a measure of lipophilicity. Two other commonly tracked physicochemical properties are the number of rotatable bonds in a molecule - a measure of flexibility - and topological polar surface area (TPSA, often shortened to just PSA). All these properties - those included in Lipinski’s rules, rotatable bonds, and TPSA - can be correlated with membrane permeability, solubility, and ultimately oral absorption.
Physicochemical properties can be combined, sometimes with experimental data, to create composite parameters. Composite parameters are often also called metrics or indices. Two of the most commonly encountered composite parameters used in lead discovery are ligand efficiency (LE) and ligand lipophilicity efficiency (LLE or LipE). Let’s discuss each of these separately.
Ligand efficiency is essentially the binding energy per heavy atom in a molecule. It can be calculated as the binding energy divided by the heavy atom count. Remember that heavy atoms include all non-hydrogen atoms in the molecule. You can also use Ki (or Kd) to calculate LE. Very often, people will use IC50 or EC50 in the calculation. That is arguably not valid, but it is good enough for the type of comparisons that people use with LE. Discovery groups typically try to keep the LE of a lead constant during an optimization campaign, and ideal values of LE are normally around 0.3 or 0.4 kcal per mol per heavy atom. Higher is better. The idea is to make sure that additional heavy atoms - additional molecular weight - are being included with a corresponding increase in binding. As much as possible, every atom in the lead should be pulling its weight and contributing to the activity of the molecule. Ligand efficiency is encountered in medicinal chemistry discussions, but it has become somewhat less popular over the years.
Ligand lipophilicity efficiency is the difference between a compound’s pIC50 (note that pIC50 is -log IC50) and the compound’s log P value. So, LLE is pIC50 minus log P. The equation for LLE demonstrates the direct tension between potency and lipophilicity. Higher LLE is considered to be better, so you want a high potency to offset lipophilicity in the compound. Lead optimization campaigns like to start with early leads with a high LLE value (maybe 4 or 5) and maintain that high LLE value throughout the optimization program.