These days there are more metrics that a supposed to lead you to the legendary "sweet spot" where all noble and pure drugs dwell than you can shake a stick at. The question arises: how many of them are actually useful as guides to drug optimization? A recent paper in Bioorganic & Medicinal Chemistry Letters tries to take a stab at assessing the usefulness of various composite parameter (ligand efficiency is probably the most commonly sighted species of said descriptor.)  

This is a quote from the paper that I find impressive.  Mainly that the author took such pains to track down all of the metrics and provide references.  I am much more lazy than the author, so you will have to read the paper to track down the references.  I will merely  provide the quote:

"Approximately 15 years ago Lipinski et al. published their seminal work linking molecular properties with oral absorption.1Since this ‘Big Bang’ of physical property analysis, the universe of parameters, rules and optimization metrics has been expanding at an ever increasing rate (Figure 1).2 Relationships with molecular weight (MW), lipophilicity,3 and 4 ionization state,5 pKa, molecular volume and total polar surface area have been examined.6 Aromatic rings,7 and 8 oxygen atoms, nitrogen atoms, sp3 carbon atoms,9 chiral atoms,9 non-hydrogen atoms, aromatic versus non-hydrogen atoms,10 aromatic atoms minus sp3 carbon atoms,6 and 11 hydrogen bond donors, hydrogen bond acceptors and rotatable bonds12 have been counted and correlated.13 In addition to the rules of five came the rules of 4/40014 and 3/75.15 Medicinal chemists can choose from composite parameters (or efficiency indices) such as ligand efficiency (LE),16 group efficiency (GE), lipophilic efficiency/lipophilic ligand efficiency (LipE17/LLE),18 ligand lipophilicity index (LLEAT),19 ligand efficiency dependent lipophilicity (LELP), fit quality scaled ligand efficiency (LE_scale),20 percentage efficiency index (PEI),21 size independent ligand efficiency (SILE), binding efficiency index (BEI) or surface binding efficiency index (SEI)22 and composite parameters are even now being used in combination.23 Efficiency of binding kinetics has recently been introduced.24 A new trend of anthropomorphizing molecular optimization has occurred as molecular ‘addictions’ and ‘obesity’ have been identified.25 To help medicinal chemists there are guideposts,21 rules of thumb,14 and 26 a property forecast index,27 graphical representations of properties28 such as efficiency maps, atlases,29 ChemGPS,30 traffic lights,31radar plots,32 Craig plots,33 flower plots,34 egg plots,35 time series plots,36 oral bioavailability graphs,37 face diagrams,28spider diagrams,38 the golden triangle39 and the golden ratio.40"


I personally have been a moderate advocate of the "Property Inquisition" method of drug discovery, finding it most useful in the selecting which hits to follow up on, rather than as a strict guide as to what to make and not to make. I have worked at companies where absolutely no attention was paid to any metric and others where chemists who made a compounds that violated the rules were publically shamed, even if they needed the compound as an SAR point.  I am interested in your experiences, dear readers.  Have you found any metric useful or particularly un-useful? Comment below, I would like to get the discussion started.  

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Since the Labor Day weekend marks the turn of the year from the light hearted playfulness of summer to a return to the routine of school and work, I thought a glimpse into the past of your humble author would be of, at least, marginal interest to you, gentle readers.  The photograph you see is me in high school.  I went to Glendora High School, in Glendora, California.  since my 30th reunion is approaching, I must admit it was 30 years ago.

In school, I was serious and studious.  I was a Valedictorian (we actually had 7) graduating with a 4.0 GPA (back then, there were no extra points for honors or AP classes). I was pathologically afraid of missing any points. I would study until I was so exhausted that I would get sick on vacations.  I never actually relaxed.  My one relief was playing Dungeons and Dragons with my small circle of close friends.  

College was easy in that I did well in all of my classes, but difficult in that I studied more than was necessary, had few friends and was very socially awkward.  I actually hated vacations, because I had little interaction with other people outside of school. 

Now, I am much more personable. Still quite scholarly.  I have, however, traveled the world. I have met and interacted with interesting and fun people everywhere I've been. If you want to find out, contact me.  I try to help everyone who does.  I also still play games just now Warhammer and Warhammer 40K :-).