Victrix Computational Chemistry and Medicinal Chemistry Consultancy
Contact us
  • Home
  • Philosophy
  • Services
  • Our Clients
  • Contact
  • About
    • Press Releases
  • Victrix Sounds Off
  • Blog

Have we gone over the top with analyses of marketed drugs and persecuting those who make compounds outside of the rule of the month?

9/4/2013

0 Comments

 
Picture
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.  

As always follow Victrix on LinkedIn if you enjoy the blog!



0 Comments



Leave a Reply.

    Adam Kallel Ph. D.

    Our CSO sounds off about drug discovery, computational chemistry and history

    Archives

    May 2018
    March 2014
    January 2014
    October 2013
    September 2013
    August 2013
    July 2013
    June 2013
    May 2013
    April 2013
    March 2013

    Categories

    All
    Ageing
    Amphetamine
    Anti-virals
    Biography
    Broken Society
    Caffeine
    Cancer
    Cd26
    Cluster Headache
    Colic
    Collaboration
    Corona Virus
    Danger Danger
    Depression
    Drug Discovery
    Drug Resistence
    Economy Of Scale
    Electron Microscopy
    Emergent Infectious Disease
    Encephalitis Lethargica
    Global Epidemiology
    Goal Setting
    HCoV-EMC
    Hiring
    Incorrect Pathologizing
    Incretin
    Influenza
    Jobs
    Me
    Merck
    Mergers
    Metabolic Disease
    Migraine
    Nerd
    Neurotransmiters
    Open Positions
    Over Prescription
    Overwork
    Pharma
    Pharmaceutical Industry
    Restructuring
    Stimulants
    Telomerase
    Tuberculosis
    Viral Replication
    Virus

    RSS Feed

    comments powered by Disqus
    View my profile on LinkedIn
Powered by Create your own unique website with customizable templates.