Impact of lipophilic efficiency on compound quality.

Lipophilic efficiency indices such as LLE and LELP were suggested to support balanced optimization of potency and ADMET profile. Here we investigated the performance of LLE and LELP on multiple data sets representing different stages of drug discovery including fragment and HTS hits and leads, development candidates, phase II compounds, and launched drugs. Analyzing their impact on ADME and safety properties and binding thermodynamics, we found that both LLE and LELP help identifying better quality compounds. LLE is sensible for the development stages but does not prefer fragment-type hits, while LELP has an advantage for this class of compounds and discriminates preferred starting points effectively. Both LLE and LELP have significant impact on ADME and safety profiles; however, LELP outperforms LLE in risk assessment at least on the present data set. On the basis of the results reported here, monitoring lipophilic efficiency metrics could contribute significantly to compound quality and might improve the output of medicinal chemistry programs.

[1]  M. Waring.  Lipophilicity in drug discovery , 2010, Expert Opinion on Drug Discovery.

[2]  N. Powell,et al.  Binding thermodynamics of substituted diaminopyrimidine renin inhibitors. , 2007, Analytical biochemistry.

[3]  Rob Leurs,et al.  Fragment growing induces conformational changes in acetylcholine-binding protein: a structural and thermodynamic analysis. , 2011, Journal of the American Chemical Society.

[4]  Brett A Tounge,et al.  Ligand efficiency and fragment-based drug discovery. , 2009, Drug discovery today.

[5]  P. Leeson,et al.  The influence of drug-like concepts on decision-making in medicinal chemistry , 2007, Nature Reviews Drug Discovery.

[6]  L. Amzel,et al.  Compensating Enthalpic and Entropic Changes Hinder Binding Affinity Optimization , 2007, Chemical biology & drug design.

[7]  Paul D. Leeson,et al.  Impact of ion class and time on oral drug molecular properties , 2011 .

[8]  Bruce Tidor,et al.  Specificity in molecular design: a physical framework for probing the determinants of binding specificity and promiscuity in a biological environment. , 2007, The journal of physical chemistry. B.

[9]  E. Freire,et al.  A Thermodynamic Approach to the Affinity Optimization of Drug Candidates , 2009, Chemical biology & drug design.

[10]  C. Murray,et al.  The rise of fragment-based drug discovery. , 2009, Nature chemistry.

[11]  J. Arrowsmith.  Trial watch: Phase II failures: 2008–2010 , 2011, Nature Reviews Drug Discovery.

[12]  Christopher W. Murray,et al.  Assessing the lipophilicity of fragments and early hits , 2011, J. Comput. Aided Mol. Des..

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

[14]  E. Freire,et al.  Adaptive inhibitors of the HIV-1 protease. , 2005, Progress in biophysics and molecular biology.

[15]  L. M. Amzel,et al.  Unique Thermodynamic Response of Tipranavir to Human Immunodeficiency Virus Type 1 Protease Drug Resistance Mutations , 2007, Journal of Virology.

[16]  Gerhard Klebe,et al.  Adding calorimetric data to decision making in lead discovery: a hot tip , 2010, Nature Reviews Drug Discovery.

[17]  John P. Overington,et al.  Probing the links between in vitro potency, ADMET and physicochemical parameters , 2011, Nature Reviews Drug Discovery.

[18]  M. Gleeson.  Generation of a set of simple, interpretable ADMET rules of thumb. , 2008, Journal of medicinal chemistry.

[19]  J. Topliss,et al.  Utilization of operational schemes for analog synthesis in drug design. , 1972, Journal of medicinal chemistry.

[20]  W Patrick Walters,et al.  What do medicinal chemists actually make? A 50-year retrospective. , 2011, Journal of medicinal chemistry.

[21]  György G Ferenczy,et al.  Thermodynamics guided lead discovery and optimization. , 2010, Drug discovery today.

[22]  M. Waring.  Defining optimum lipophilicity and molecular weight ranges for drug candidates-Molecular weight dependent lower logD limits based on permeability. , 2009, Bioorganic & medicinal chemistry letters.

[23]  J. Hughes,et al.  Physiochemical drug properties associated with in vivo toxicological outcomes. , 2008, Bioorganic & medicinal chemistry letters.

[24]  Alexander A Alex,et al.  Fragment-based drug discovery: what has it achieved so far? , 2007, Current topics in medicinal chemistry.

[25]  George M. Whitesides,et al.  Mechanism of the hydrophobic effect in the biomolecular recognition of arylsulfonamides by carbonic anhydrase , 2011, Proceedings of the National Academy of Sciences.

[26]  E. Freire,et al.  Binding thermodynamics of statins to HMG-CoA reductase. , 2005, Biochemistry.

[27]  Brett A Tounge,et al.  The role of molecular size in ligand efficiency. , 2007, Bioorganic & medicinal chemistry letters.

[28]  P. Verhoest,et al.  Defining desirable central nervous system drug space through the alignment of molecular properties, in vitro ADME, and safety attributes. , 2010, ACS chemical neuroscience.

[29]  M. Hann.  Molecular obesity, potency and other addictions in drug discovery , 2011 .

[30]  D. Piomelli.  Responses to stress: from the periphery to the brain. , 2009, Current opinion in pharmacology.

[31]  György M. Keserü,et al.  The influence of lead discovery strategies on the properties of drug candidates , 2009, Nature Reviews Drug Discovery.

[32]  Laszlo Urban,et al.  Maximising use of in vitro ADMET tools to predict in vivo bioavailability and safety , 2007, Expert opinion on drug metabolism & toxicology.

[33]  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.

[34]  Michèle N Schulz,et al.  Recent progress in fragment-based lead discovery. , 2009, Current opinion in pharmacology.

[35]  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.