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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

Scoring Ligand Efficiency: Potency, Ligand Efficiency and Product Ligand Efficiency within Big Data Landscape

Author(s): Jaroslaw Polanski*, Anna Pedrys, Roksana Duszkiewicz and Johann Gasteiger

Volume 16, Issue 11, 2019

Page: [1258 - 1263] Pages: 6

DOI: 10.2174/1570180816666190112154505

Price: $65

Abstract

Background: Potency is the broadest available biological activity data type. In turn, Ligand Efficiency (LE) is a molecular descriptor that probes the ratio of potency vs Heavy Atom Count (HAC), which emphasizes low HAC more than potency and thus has drawbacks as an estimator of drug candidates. The objective was to design a novel transform to probe potency and HAC interaction in which potency and HAC would be balanced more evenly.

Methods: In this study, potency data of ChEMBL, PubChem, FDA approvals and drug (fragments) were analysed. A novel descriptor, a product of the pAC50 value with HAC, multiplicative or Product Ligand Efficiency (PLE) was designed and tested.

Results: In particular PLE was compared with pAC50 and LE vs the HAC statistics for different series of ligands. This indicated that PLE is an informative estimator that can be used to recognize the potential of drugs. PLE has a maximum value in the range around 30-50 HAC.

Conclusion: Drug design is a complex problem. Similarly, to drug-likeness, LE prefers small molecules. This makes LE a tool serendipitously improving drug likeness. In this context, LE performs unexpectedly well even despite the uncertainty of its physical meaning. PLE is a more evenly balanced estimator whose physical meaning is the Minimum Inhibitory Concentration (MIC).

Keywords: Ligand efficiency, product ligand efficiency, heavy atom count, activity, drug design, pubchem, chembl.

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[1]
Hopkins, A.L.; Keserü, G.M.; Leeson, P.D.; Rees, D.C.; Reynolds, C.H. The role of ligand efficiency metrics in drug discovery. Nat. Rev. Drug Discov., 2014, 13(2), 105-121.
[http://dx.doi.org/10.1038/nrd4163] [PMID: 24481311]
[2]
Williams, G.; Ferenczy, G.G.; Ulander, J.; Keserű, G.M. Binding thermodynamics discriminates fragments from druglike compounds: A thermodynamic description of fragment-based drug discovery. Drug Discov. Today, 2017, 22(4), 681-689.
[http://dx.doi.org/10.1016/j.drudis.2016.11.019] [PMID: 27916639]
[3]
Hann, M.M.; Leach, A.R.; Harper, G. Molecular complexity and its impact on the probability of finding leads for drug discovery. J. Chem. Inf. Comput. Sci., 2001, 41(3), 856-864.
[http://dx.doi.org/10.1021/ci000403i] [PMID: 11410068]
[4]
Zartler, E.R.; Shapiro, M.J. Fragonomics: Fragment-based drug discovery. Curr. Opin. Chem. Biol., 2005, 9(4), 366-370.
[http://dx.doi.org/10.1016/j.cbpa.2005.05.002] [PMID: 15925537]
[5]
Kuntz, I.D.; Chen, K.; Sharp, K.A.; Kollman, P.A. The maximal affinity of ligands. Proc. Natl. Acad. Sci. USA, 1999, 96(18), 9997-10002.
[http://dx.doi.org/10.1073/pnas.96.18.9997] [PMID: 10468550]
[6]
Reynolds, C.H.; Bembenek, S.D.; Tounge, B.A. The role of molecular size in ligand efficiency. Bioorg. Med. Chem. Lett., 2007, 17(15), 4258-4261.
[http://dx.doi.org/10.1016/j.bmcl.2007.05.038] [PMID: 17532632]
[7]
Reynolds, C.H.; Tounge, B.A.; Bembenek, S.D. Ligand binding efficiency: Trends, physical basis, and implications. J. Med. Chem., 2008, 51(8), 2432-2438.
[http://dx.doi.org/10.1021/jm701255b] [PMID: 18380424]
[8]
Reynolds, C.H.; Reynolds, R.C. Group additivity in ligand binding affinity: An alternative approach to ligand efficiency. J. Chem. Inf. Model., 2017, 57(12), 3086-3093.
[http://dx.doi.org/10.1021/acs.jcim.7b00381] [PMID: 29111708]
[9]
Shultz, M.D. Improving the plausibility of success with inefficient metrics. ACS Med. Chem. Lett., 2013, 5(1), 2-5.
[http://dx.doi.org/10.1021/ml4004638] [PMID: 24900765]
[10]
Shultz, M.D. Setting expectations in molecular optimizations: Strengths and limitations of commonly used composite parameters. Bioorg. Med. Chem. Lett., 2013, 23(21), 5980-5991.
[http://dx.doi.org/10.1016/j.bmcl.2013.08.029] [PMID: 24018190]
[11]
Zhou, H.X.; Gilson, M.K. Theory of free energy and entropy in noncovalent binding. Chem. Rev., 2009, 109(9), 4092-4107.
[http://dx.doi.org/10.1021/cr800551w] [PMID: 19588959]
[12]
Murray, C.W.; Erlanson, D.A.; Hopkins, A.L.; Keserü, G.M.; Leeson, P.D.; Rees, D.C.; Reynolds, C.H.; Richmond, N.J. Validity of ligand efficiency metrics. ACS Med. Chem. Lett., 2014, 5(6), 616-618.
[http://dx.doi.org/10.1021/ml500146d] [PMID: 24944729]
[13]
Polanski, J.; Tkocz, A.; Kucia, U. Beware of ligand efficiency (LE): understanding LE data in modeling structure-activity and structure-economy relationships. J. Cheminform., 2017, 9(1), 49.
[http://dx.doi.org/10.1186/s13321-017-0236-9] [PMID: 29086197]
[14]
Polanski, J.; Tkocz, A. Between descriptors and properties: Understanding the ligand efficiency trends for g protein-coupled receptor and kinase structure-activity data sets. J. Chem. Inf. Model., 2017, 57(6), 1321-1329.
[http://dx.doi.org/10.1021/acs.jcim.7b00116] [PMID: 28489365]
[15]
Sheridan, R.P. Debunking the idea that ligand efficiency indices are superior to pIC50 as QSAR activities. J. Chem. Inf. Model., 2016, 56(11), 2253-2262.
[http://dx.doi.org/10.1021/acs.jcim.6b00431] [PMID: 27766848]
[16]
Polanski, J.; Gasteiger, J. Computer representation of chemical compounds.Handbook of Computational Chemistry; Leszczynski, J., Ed.; Springer: Dordrecht, 2016.
[17]
Schultes, S.; de Graaf, C.; Haaksma, E.; de Esch, I.; Leurs, R.; Krämer, O. Ligand efficiency as a guide in fragment hit selection and optimization. Drug Discov. Today. Technol., 2010, 7, e157-e162.
[http://dx.doi.org/10.1016/j.ddtec.2010.11.003]
[18]
Klebe, G. Applying thermodynamic profiling in lead finding and optimization. Nat. Rev. Drug Discov., 2015, 14(2), 95-110.
[http://dx.doi.org/10.1038/nrd4486] [PMID: 25614222]
[19]
Polanski, J.; Kucia, U.; Duszkiewicz, R.; Kurczyk, A.; Magdziarz, T.; Gasteiger, J. Molecular descriptor data explain market prices of a large commercial chemical compound library. Sci. Rep., 2016, 6, 28521.
[http://dx.doi.org/10.1038/srep28521] [PMID: 27334348]

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