Journal of Computer-Aided Molecular Design

, Volume 28, Issue 7, pp 699–710 | Cite as

Ligand efficiency metrics considered harmful

  • Peter W. Kenny
  • Andrei Leitão
  • Carlos A. Montanari
Perspective

Abstract

Ligand efficiency metrics are used in drug discovery to normalize biological activity or affinity with respect to physicochemical properties such as lipophilicity and molecular size. This Perspective provides an overview of ligand efficiency metrics and summarizes thermodynamics of protein–ligand binding. Different classes of ligand efficiency metric are critically examined and the study concludes with suggestions for alternative ways to account for physicochemical properties when prioritizing and optimizing leads.

Keywords

Acid/base properties Ligand efficiency Lipophilic efficiency Metric Property-based design 

References

  1. 1.
    Hopkins AL, Keserü GM, Leeson PD, Rees DC, Reynolds CH (2014) The role of ligand efficiency metrics in drug discovery. Nat Rev Drug Discov 13:105–121CrossRefGoogle Scholar
  2. 2.
    Kenny PW, Montanari CA, Prokopczyk IM (2013) ClogPalk: a method for predicting alkane/water partition coefficient. J Comput Aided Mol Des 27:389–402CrossRefGoogle Scholar
  3. 3.
    Schultz MD (2013) Setting expectations in molecular optimizations: strengths and limitations of commonly used composite parameters. Bioorg Med Chem Lett 23:5980–5991Google Scholar
  4. 4.
    Schultz MD (2014) Improving the plausibility of success with inefficient metrics. ACS Med Chem Lett 5:2–5CrossRefGoogle Scholar
  5. 5.
    Kenny PW, Montanari CA, Prokopczyk IM, Sala FA, Sartori GR (2013) Automated molecule editing in molecular design. J Comput Aided Mol Des 27:655–664CrossRefGoogle Scholar
  6. 6.
    Kenny PW (2009) Hydrogen bonding, electrostatic potential and molecular design. J Chem Inf Model 49:1234–1244CrossRefGoogle Scholar
  7. 7.
    Linusson A, Gottfries J, Lindgren F, Wold S (2000) Statistical molecular design of building blocks for combinatorial chemistry. J Med Chem 43:1320–1328CrossRefGoogle Scholar
  8. 8.
    van de Waterbeemd H, Smith DA, Beaumont K, Walker DK (2001) Property-based design: optimization of drug absorption and pharmacokinetics. J Med Chem 44:1313–1333CrossRefGoogle Scholar
  9. 9.
    Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 23:3–25CrossRefGoogle Scholar
  10. 10.
    Kenny PW, Montanari CA (2013) Inflation of correlation in the pursuit of drug-likeness. J Comput Aided Mol Des 27:1–13CrossRefGoogle Scholar
  11. 11.
    Muthas D, Boyer S, Hasselgren C (2013) A critical assessment of modeling safety-related drug attrition. Med Chem Commun 4:1058–1065CrossRefGoogle Scholar
  12. 12.
    Erlanson DA, McDowell RS, O’Brien T (2004) Fragment-based drug discovery. J Med Chem 47:3463–3482CrossRefGoogle Scholar
  13. 13.
    Leach AR, Hann MM, Burrows JN, Griffen EJ (2006) Fragment screening: an introduction. Mol BioSyst 2:429–446CrossRefGoogle Scholar
  14. 14.
    Hajduk PJ (2006) Fragment-based drug design: how big is too big? J Med Chem 49:6972–6976CrossRefGoogle Scholar
  15. 15.
    Albert JS, Blomberg N, Breeze AL, Brown AJH, Burrows JN, Edwards PD, Folmer RHA, Geschwindner S, Griffen EJ, Kenny PW, Nowak T, Olsson L, Sanganee H, Shapiro AB (2007) An integrated approach to fragment-based lead generation: philosophy, strategy and case studies from AstraZeneca’s drug discovery programs. Curr Top Med Chem 7:1600–1629CrossRefGoogle Scholar
  16. 16.
    Congreve M, Chessari G, Tisi D, Woodhead AJ (2008) Recent developments in fragment-based drug discovery. J Med Chem 51:3661–3680CrossRefGoogle Scholar
  17. 17.
    Blomberg N, Cosgrove DA, Kenny PW, Kolmodin K (2009) Design of compound libraries for fragment screening. J Comput Aided Mol Des 23:513–525CrossRefGoogle Scholar
  18. 18.
    Erlanson DA (2012) Introduction to fragment-based drug discovery. Top Curr Chem 317:1–32CrossRefGoogle Scholar
  19. 19.
    Joseph-McCarthy D, Campbell AJ, Kern G, Moustakas D (2014) Fragment-based lead discovery and design. J Chem Inf Model 54:693–704CrossRefGoogle Scholar
  20. 20.
    Abad-Zapatero C, Perišić O, Wass J, Bento AP, Overington J, Al-Lazikani B, Johnson ME (2010) Ligand efficiency indices for an effective mapping of chemico-biological space: the concept of an atlas-like representation. Drug Discov Today 15:805–811Google Scholar
  21. 21.
    Abad-Zapatero C, Champness EJ, Segall MD (2014) Alternative variables in drug discovery: promises and challenges. Future Med Chem 6:577–593CrossRefGoogle Scholar
  22. 22.
    Smith DA, Di L, Kerns EH (2010) The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery. Nat Rev Drug Discov 9:929–939CrossRefGoogle Scholar
  23. 23.
    Hopkins AL, Groom CR, Alex A (2004) Ligand efficiency: a useful metric for lead selection. Drug Discov Today 9:430–431CrossRefGoogle Scholar
  24. 24.
    Tropsha A (2011) Best practices for QSAR model development, validation and exploitation. Mol Inform 29:476–488CrossRefGoogle Scholar
  25. 25.
    Gilson MK, Given JA, Bush BL, McCammon JA (1997) The statistical-thermodynamic basis for computation of binding affinities: a critical review. Biophys J 72:1047–1069CrossRefGoogle Scholar
  26. 26.
    Zhou H-X, Gilson MK (2009) Theory of free energy and entropy in noncovalent binding. Chem Rev 109:4092–4107CrossRefGoogle Scholar
  27. 27.
    Gilson MK, Zhou H-X (2011) Calculation of protein-ligand binding affinities. Annu Rev Biophys Biomol Struct 36:21–42CrossRefGoogle Scholar
  28. 28.
    Mortenson PN, Murray CW (2011) Assessing the lipophilicity of fragments and early hits. J Comput Aided Mol Des 25:663–667CrossRefGoogle Scholar
  29. 29.
    Kuntz ID, Chen K, Sharp KA, Kollman PA (1999) The maximal affinity of ligands. Proc Natl Acad Sci 96:9997–10002CrossRefGoogle Scholar
  30. 30.
    Smith RD, Engdahl AL, Dunbar JB, Carlson HA (2012) Biophysical limits of protein-ligand binding. J Chem Inf Model 52:2098–2106CrossRefGoogle Scholar
  31. 31.
    Abraham MH (1993) Scales of solute hydrogen-bonding: their construction and application to physicochemical and biochemical processes. Chem Soc Rev 22:73–83CrossRefGoogle Scholar
  32. 32.
    Bissantz C, Kuhn B, Stahl M (2010) A medicinal chemist’s guide to molecular interactions. J Med Chem 53:5061–5084CrossRefGoogle Scholar
  33. 33.
    Hann MM, Leach AR, Harper G (2001) Molecular complexity and its impact on the probability of finding leads for drug discovery. J Chem Inf Comp Sci 41:856–864CrossRefGoogle Scholar
  34. 34.
    Reynolds CH, Tounge BA, Bembenek SD (2008) Ligand binding efficiency: trends, physical basis, and implications. J Med Chem 51:2432–2438CrossRefGoogle Scholar
  35. 35.
    Williams JW, Morrison JF (1979) The kinetics of reversible tight-binding inhibition. Methods Enymol 63:437–467CrossRefGoogle Scholar
  36. 36.
    Abad-Zapatero C, Metz JT (2005) Ligand efficiency indices as guideposts for drug discovery. Drug Discov Today 10:465–469Google Scholar
  37. 37.
    Lloyd G, Czaplewskia LG, Collins I, Boyd EA, Brown D, East SP, Gardiner M, Fletcher R, Haydon DJ, Henstock V, Ingram P, Jones C, Noula C, Kennison L, Rockley C, Rose V, Thomaides-Brears HB, Ure R, Whittaker M, Stokes NR (2009) Antibacterial alkoxybenzamide inhibitors of the essential bacterial cell division protein FtsZ. Bioorg Med Chem Lett 19:524–527CrossRefGoogle Scholar
  38. 38.
    Ladbury JE, Klebe G, Freire E (2010) Adding calorimetric data to decision making in lead discovery: a hot tip. Nat Rev Drug Discov 9:23–27CrossRefGoogle Scholar
  39. 39.
    Lewis ML, Cucurull-Sanchez L (2009) Structural pairwise comparisons of HLM stability of phenyl derivatives: introduction of the Pfizer metabolism index (PMI) and metabolism-lipophilicity efficiency (MLE). J Comput Aided Mol Des 23:97–103Google Scholar
  40. 40.
    Holdgate GA, Gill AL (2011) Kinetic efficiency: the missing metric for enhancing compound quality? Drug Discov Today 16:910–913CrossRefGoogle Scholar
  41. 41.
    Murray CW, Erlanson DA, Hopkins AL, Keserü GM, Leeson PD, Rees DC, Reynolds CH, Richmond NJ (2014) Validity of ligand efficiency metrics. ACS Med Chem Lett ASAP. 10.1021/ml500146d
  42. 42.
    Verdonk ML, Rees DC (2008) Group efficiency: a guideline for hits-to-leads chemistry. ChemMedChem 3:1179–1180CrossRefGoogle Scholar
  43. 43.
    Leeson PD, Springthorpe B (2007) The influence of drug-like concepts on decision-making in medicinal chemistry. Nat Rev Drug Discov 6:881–890CrossRefGoogle Scholar
  44. 44.
    Ryckmans T, Edwards MP, Horne VA, Correia AM, Owen DR, Thompson LR, Tran I, Tutt MF, Young T (2009) Rapid assessment of a novel series of selective CB2 agonists using parallel synthesis protocols: a lipophilic efficiency (LipE) analysis. Bioorg Med Chem Lett 19:4406–4409CrossRefGoogle Scholar
  45. 45.
    Keserü GM, Makara GM (2009) The influence of lead discovery strategies on the properties of drug candidates. Nat Rev Drug Discov 8:203–212CrossRefGoogle Scholar
  46. 46.
    Freeman-Cook KD, Hoffman RL, Johnson TW (2013) Lipophilic efficiency: the most important efficiency metric in medicinal chemistry. Future Med Chem 5:113–115CrossRefGoogle Scholar
  47. 47.
    Mannhold R, Poda GI, Ostermann C, Tetko IV (2009) Calculation of molecular lipophilicity: state-of-the-art and comparison of log P methods on more than 96,000 compounds. J Pharm Sci 98:861–893CrossRefGoogle Scholar
  48. 48.
    Valko K, Chiaparin E, Nunhuck S, Montanari D (2012) In vitro measurement of drug efficiency index to aid early lead optimization. J Pharm Sci 101:4155–4169CrossRefGoogle Scholar
  49. 49.
    McTigue M, Murray BW, Jeffrey H. Chen JH, Denga Y-L, Solowiej J, Kania RS (2012) Molecular conformations, interactions, and properties associated with drug efficiency and clinical performance among VEGFR TK inhibitors. Proc Nat Acad Sci109:18281–18289Google Scholar
  50. 50.
    Schultz MD (2013) The thermodynamic basis for the use of lipophilic efficiency (LipE) in enthalpic optimizations. Bioorg Med Chem Lett 23:5992–6000CrossRefGoogle Scholar
  51. 51.
    Abraham MH, Chadha HS, Whiting GS, Mitchell RC (1994) Hydrogen bonding. 32. An analysis of water-octanol and water-alkane partitioning and the ΔlogP parameter of Seiler. J Pharm Sci 83:1085–1100CrossRefGoogle Scholar
  52. 52.
    Manallack DT, Prankerd RJ, Yuriev E, Oprea TI, Chalmers DK (2013) The significance of acid/base properties in drug discovery. Chem Soc Rev 42:485–496CrossRefGoogle Scholar
  53. 53.
    Bell PH, Roblin RO (1942) Studies in chemotherapy. VII. A theory of the relation of structure to activity of sulfanilamide type compounds. J Am Chem Soc 64:2905–2917CrossRefGoogle Scholar
  54. 54.
    Taylor PJ, Wait AR (1986) σi Values for heterocycles. J Chem Soc Perkin Trans 2:1765–1770CrossRefGoogle Scholar
  55. 55.
    Tarcsay A, Nyiri K, Keserű GM (2012) Impact of lipophilic efficiency on compound quality. J Med Chem 55:1252–1260CrossRefGoogle Scholar
  56. 56.
    Kalivas J (1999) Interrelationships of multivariate regression methods using eigenvector basis sets. J Chemom 13:111–132CrossRefGoogle Scholar
  57. 57.
    Maggiora GM (2006) On outliers and activity cliffs—why QSAR often disappoints. J Chem Inf Model 46:1535CrossRefGoogle Scholar
  58. 58.
    Guha R, Van Drie JH (2008) Structure-activity landscape index: identifying and quantifying activity cliffs. J Chem Inf Model 48:646–658CrossRefGoogle Scholar
  59. 59.
    Stumpfe D, Bajorath J (2012) Exploring activity cliffs in medicinal chemistry. J Med Chem 55:2932–2942CrossRefGoogle Scholar
  60. 60.
    DeLano WL (2002) Unraveling hot spots in binding interfaces: progress and challenges. Curr Opin Struct Biol 12:14–20CrossRefGoogle Scholar
  61. 61.
    Black E, Breed J, Breeze AL, Embrey K, Garcia R, Gero TW, Godfrey L, Kenny PW, Morley AD, Minshull CA, Pannifer AD, Read J, Rees A, Russell DJ, Toader D, Tucker J (2005) Structure-based design of protein tyrosine phosphatase-1B inhibitors. Bioorg Med Chem Lett 15:2503–2507CrossRefGoogle Scholar
  62. 62.
    Lind E (2010) QSAR analysis involving assay results which are only known to be greater than, or less than some cut-off limit. Mol Inform 29:845–852CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Peter W. Kenny
    • 1
  • Andrei Leitão
    • 1
  • Carlos A. Montanari
    • 1
  1. 1.Grupo de em Química Medicinal do IQSC/USP – NEQUIMED, Instituto de Química de São CarlosUniversidade de São PauloSão CarlosBrazil

Personalised recommendations