Ligand Efficiency Indices (LEIs): More than a Simple Efficiency Yardstick

The concept of ligand efficiency and the usage of ligand efficiency values to assess the quality of fragments and compounds is becoming more accepted in the practice of medicinal chemistry. This is particularly true as it refers to the efficiency of ligands per unit size (i.e., binding affinity/number of non‐hydrogen atoms or binding affinity/MW). The use of the Ligand Efficiency Indices (LEIs) as variables for a Cartesian mapping of chemico‐biological space, the concept of AtlasCBS, has been presented in a recent publication with some initial drug‐discovery applications. In this communication, we present additional applications of the concept in three domains of drug discovery: i) analyze and compare the content of databases: inhibitors vs. drugs; ii) polypharmacology; and iii) applications to Fragment‐Based strategies. We suggest that the combined use of LEIs in a Cartesian representation of Chemico‐Biological Space (AtlasCBS) could be a useful tool in various aspects of drug‐discovery in the future.

[1]  T I Oprea,et al.  Cheminformatics: a tool for decision-makers in drug discovery. , 2001, Current opinion in drug discovery & development.

[2]  John P. Overington,et al.  Ligand efficiency indices for an effective mapping of chemico-biological space: the concept of an atlas-like representation. , 2010, Drug discovery today.

[3]  Wendy A. Warr,et al.  ChEMBL. An interview with John Overington, team leader, chemogenomics at the European Bioinformatics Institute Outstation of the European Molecular Biology Laboratory (EMBL-EBI) , 2009, J. Comput. Aided Mol. Des..

[4]  M. Gilson,et al.  Calculation of protein-ligand binding affinities. , 2007, Annual review of biophysics and biomolecular structure.

[5]  M. Congreve,et al.  Recent developments in fragment-based drug discovery. , 2008, Journal of medicinal chemistry.

[6]  Renxiao Wang,et al.  The PDBbind database: collection of binding affinities for protein-ligand complexes with known three-dimensional structures. , 2004, Journal of medicinal chemistry.

[7]  Dan C. Fara,et al.  Lead-like, drug-like or “Pub-like”: how different are they? , 2007, J. Comput. Aided Mol. Des..

[8]  John P. Overington,et al.  How many drug targets are there? , 2006, Nature Reviews Drug Discovery.

[9]  C. Abad-Zapatero,et al.  Ligand efficiency indices for effective drug discovery , 2007, Expert opinion on drug discovery.

[10]  Tudor I. Oprea,et al.  Chemography: the Art of Navigating in Chemical Space , 2000 .

[11]  A. Hopkins,et al.  Ligand efficiency: a useful metric for lead selection. , 2004, Drug discovery today.

[12]  Tudor I. Oprea,et al.  Chemical space navigation in lead discovery. , 2002, Current opinion in chemical biology.

[13]  Ian M. Eggleston,et al.  Structure-Based Dissection of the Natural Product Cyclopentapeptide Chitinase Inhibitor Argifin , 2008, Chemistry & biology.

[14]  M. Congreve,et al.  A 'rule of three' for fragment-based lead discovery? , 2003, Drug discovery today.

[15]  C. Lipinski.  Drug-like properties and the causes of poor solubility and poor permeability. , 2000, Journal of pharmacological and toxicological methods.

[16]  J. Mestres,et al.  Conciliating binding efficiency and polypharmacology. , 2009, Trends in pharmacological sciences.

[17]  Xin Wen,et al.  BindingDB: a web-accessible database of experimentally determined protein–ligand binding affinities , 2006, Nucleic Acids Res..

[18]  J. T. Metz,et al.  Ligand efficiency indices as guideposts for drug discovery. , 2005, Drug discovery today.

[19]  Tudor I. Oprea,et al.  An automated PLS search for biologically relevant QSAR descriptors , 2004, J. Comput. Aided Mol. Des..

[20]  P. Hajduk,et al.  A decade of fragment-based drug design: strategic advances and lessons learned , 2007, Nature Reviews Drug Discovery.

[21]  Renxiao Wang,et al.  The PDBbind database: methodologies and updates. , 2005, Journal of medicinal chemistry.

[22]  P. Hajduk.  Fragment-based drug design: how big is too big? , 2006, Journal of medicinal chemistry.

[23]  A. Hopkins,et al.  Navigating chemical space for biology and medicine , 2004, Nature.

[24]  Emanuele Perola,et al.  An analysis of the binding efficiencies of drugs and their leads in successful drug discovery programs. , 2010, Journal of medicinal chemistry.