Solubility Issues in Early Discovery and HTS

  • LI DI
Part of the Biotechnology: Pharmaceutical Aspects book series (PHARMASP, volume VI)


Drug discovery programs begin with target identification and validation for diseases with unmet medical needs (Figure 1). Drug discovery targets that are currently available mostly fall into two categories, with 45% being receptors and 28% being enzymes (Table 1) (Drews, 2000). There are only 483 targets addressed by all drugs in the pharmaceutical industry, which is a relatively small number compared to the estimated 3000–10,000 disease relevant genes (Meisner et al., 2004). It is evident that the drug target universe is far from being fully exploited.


High Throughput Screening Aqueous Buffer Assay Medium Insoluble Compound Receptor Binding Assay 
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  1. Andreani A, Cavalli A, Granaiola M, Guardigli M, Leoni A, Locatelli A, Morigi R, Rambaldi M, Recanatini M, and Roda A. Synthesis and Screening for Antiacetylcholinesterase Activity of (1-Benzyl-4-oxopiperidin-3-ylidene)methylindoles and -pyrroles Related to Donepezil. J Med Chem. 2001; 44: 4011–4014.PubMedCrossRefGoogle Scholar
  2. Avdeef A. Physicochemical Profiling (Solubility, Permeability and Charge State). Curr Top Med Chem 2001; 1: 277–351.PubMedCrossRefGoogle Scholar
  3. Balakin KV. DMSO Solubility and Bioscreening. Curr Drug Discov 2003; 27–30.Google Scholar
  4. Balakin KV, Ivanenkov YA, Skorenko AV, Nikolsky YV, Savchuk NP, and Ivashchenko AA. In Silico Estimation of DMSO Solubility of Organic Compounds for Bioscreening. J Biomol Screen 2004; 9: 22–31.PubMedCrossRefGoogle Scholar
  5. Benson N, Boyd HF, Everett JR, Fries J, Gribbon P, Haque N, Henco K, Jessen T, Martin WH, Mathewson TJ, Sharp RE, Spencer RW, Stuhmeier F, Wallace MS, and Winkler D. NanoStore: A Concept for Logistical Improvements of Compound Handling in High-Throughput Screening. J Biomol Screen 2005; 10: 573–580.PubMedCrossRefGoogle Scholar
  6. Bevan CD and Lloyd RS. A High-Throughput Screening Method for the Determination of Aqueous Drug Solubility Using Laser Nephelometry in Microtiter Plates. Anal Chem 2000; 72: 1781–1787.PubMedCrossRefGoogle Scholar
  7. Blackman MJ, Corrie JET, Croney JC, Kelly G, Eccleston JF, and Jameson DM. Structural and Biochemical Characterization of a Fluorogenic Rhodamine-Labeled Malarial Protease Substrate. Biochemistry 2002; 41: 12244–12252.PubMedCrossRefGoogle Scholar
  8. Bleicher KH, Bohm H-J, Muller K, and Alanine AI. Hit and Lead Generation: Beyond High-Throughput Screening. Nat Rev Drug Discov 2003; 2: 369–378.PubMedCrossRefGoogle Scholar
  9. Buchli R, VanGundy RS, Hickman-Miller HD, Giberson CF, Bardet W, and Hildebrand WH, Development and Validation of a Fluorescence Polarization-Based Competitive Peptide-Binding Assay for HLA-A*0201-A New Tool for Epitope Discovery. Biochemistry 2005; 44: 12491–12507.PubMedCrossRefGoogle Scholar
  10. Cheng X, Hochlowski J, Tang H, Hepp D, Beckner C, Kantor S, and Schmitt R. Studies on Repository Compound Stability in DMSO under Various Conditions. J Biomol Screen 2003; 8: 292–304.PubMedCrossRefGoogle Scholar
  11. Dalvit C, Flocco M, Knapp S, Mostardini M, Perego R, Stockman BJ, Veronesi M, and Varasi M. High-Throughput NMR-Based Screening with Competition Binding Experiments. J Am Chem Soc 2002; 124: 7702–7709.PubMedCrossRefGoogle Scholar
  12. Davidson W, Frego L, Peet GW, Kroe RR, Labadia ME, Lukas SM, Snow RJ, Jakes S, Grygon CA, Pargellis C, and Werneburg BG. Discovery and Characterization of a Substrate Selective p38 Inhibitor. Biochemistry 2004; 43: 11658–11671.PubMedCrossRefGoogle Scholar
  13. Dean KES, Klein G, Renaudet O, and Reymond J-L. A Green Fluorescent Chemosensor for Amino Acids Provides a Versatile High-throughput Screening (HTS) Assay for Proteases. Bioorg Med Chem Lett 2003; 13: 1653–1656.PubMedCrossRefGoogle Scholar
  14. Delaney JS. Predicting Aqueous Solubility from Structure. Drug Discov Today 2005; 10: 289–295.PubMedCrossRefGoogle Scholar
  15. Di L and Kerns EH. Application of Pharmaceutical Profiling Assays for Optimization of Drug-like Properties. Curr Opin Drug Discov & Devel 2005; 8: 495–504.Google Scholar
  16. Dickson M and Gagnon JP. Key Factors in the Rising Cost of New Drug Discovery and Development. Nat Rev Drug Discov 2004; 3: 417–429.PubMedCrossRefGoogle Scholar
  17. Drews J. Drug Discovery: A Historical Perspective. Science 2000; 287: 1960–1964.PubMedCrossRefGoogle Scholar
  18. Faria TN, Timoszyk JK, Stouch TR, Vig BS, Landowski CP, Amidon GL, Weaver CD, Wall DA, and Smith RL. A Novel High-Throughput PepT1 Transporter Assay Differentiates between Substrates and Antagonists. Mol Pharm 2004; 1: 67–76.PubMedCrossRefGoogle Scholar
  19. Feng BY, Shelat A, Doman TN, Guy RK, and Shoichet BK. High-throughput assays for promiscuous inhibitors. Nat Chem Biol 2005; 1: 146–148.PubMedCrossRefGoogle Scholar
  20. Fillers WS. Compound Libraries—Cost of Ownership. Drug Discov World 2004; 5: 86–90.Google Scholar
  21. Gezginci MH, Martin AR, and Franzblau SG. Antimycobacterial Activity of Substituted Isosteres of Pyridine- and Pyrazinecarboxylic Acids. J Med Chem 2001; 44: 1560–1563.PubMedCrossRefGoogle Scholar
  22. Glomme A, März J, and Dressman JB. Comparison of a Miniaturized Shake-Flask Solubility Method with Automated Potentiometric Acid/Base Titrations and Calculated Solubilities. J Pharm Sci 2005; 94: 1–16.PubMedCrossRefGoogle Scholar
  23. Goodwin JJ. Flow Cell System for Solubility Testing, in p 12 pp, (Becton, Dickinson and Company, USA). Application: EP, 2003.Google Scholar
  24. Gribbon P and Andreas S. High-throughput Drug Discovery: What Can We Expect from HTS? Drug Discov Today 2005; 10: 17–22.PubMedCrossRefGoogle Scholar
  25. Hertzberg RP and Pope AJ. High-throughput Screening: New Technology for the 21st Century. Curr Opin Chem Biol 2000; 4: 445–451.PubMedCrossRefGoogle Scholar
  26. Hoever M and Zbinden P. The Evolution of Microarrayed Compound Screening. Drug Discov Today 2004; 9: 358–365.PubMedCrossRefGoogle Scholar
  27. Japertas P, Verheij H, and Petrauskas A. DMSO Solubility Prediction. LogP 2004, Zurich, Switzerland, 2004.Google Scholar
  28. Johnston PA and Johnston PA. Cellular Platforms for HTS: Three Case Studies. Drug Discov Today 2002; 7: 353–363.PubMedCrossRefGoogle Scholar
  29. Jorgensen WL and Duffy EM. Prediction of Drug Solubility from Structure. Adv Drug Deliv Rev 2002; 54: 355–366.PubMedCrossRefGoogle Scholar
  30. Kerns EH. High Throughput Physicochemical Profiling for Drug Discovery. J Pharm Sci 2001; 90: 1838–1858.PubMedCrossRefGoogle Scholar
  31. Kerns EH and Di L. Physicochemical Profiling: Overview of the Screens. Drug Discovery Today: Technologies 2004; 1: 343–348.CrossRefGoogle Scholar
  32. Kerns EH and Di L. Automation in Pharmaceutical Profiling. J Association for Laboratory Automation 2005; 10: 114–123.CrossRefGoogle Scholar
  33. Kerns EH, Di L, Bourassa J, Gross J, Huang N, Liu H, Kleintop T, Nogle L, Mallis L, Petucci C, Petusky S, Tischler M, Sabus C, Sarkahian A, Young M, Zhang M-y, Huryn D, McConnell O, and Carter G. Integrity Profiling of High Throughput Screening Hits Using LC-MS and Related Techniques. Comb Chem High Throughput Screen 2005; 8: 459–466.PubMedCrossRefGoogle Scholar
  34. Kozikowski BA, Burt TM, Tirey DA, Williams LE, Kuzmak BR, Stanton DT, Morand KL, and Nelson SL. The Effect of Freeze/Thaw Cycles on the Stability of Compounds in DMSO. J Biomol Screen 2003a; 8: 210–215.CrossRefGoogle Scholar
  35. Kozikowski BA, Burt TM, Tirey DA, Williams LE, Kuzmak BR, Stanton DT, Morand KL, and Nelson SL. The Effect of Room-Temperature Storage on the Stability of Compounds in DMSO. J Biomol Screen 2003b; 8: 205–209.CrossRefGoogle Scholar
  36. Lipinski C. Solubility in the Design of Combinatorial Libraries. Chem Anal, New York 2004a; 163: 407–434.Google Scholar
  37. Lipinski CA. Avoiding Investment in Doomed Drugs. Curr Drug Discov 2001; 17–19.Google Scholar
  38. Lipinski CA. Solubility in Water and DMSO: Issues and Potential Solutions. Biotechnology: Pharmaceutical Aspects 2004b; 1: 93–125.Google Scholar
  39. Lipinski CA and Hoffer E. Compound Properties and Drug Quality. Practice of Medicinal Chemistry (2nd Edition) 2003, pp. 341–349.Google Scholar
  40. Lipinski CA, Lombardo F, Dominy BW and Feeney PJ. Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings. Advanced Drug Delivery Reviews 1997; 23:3–25.CrossRefGoogle Scholar
  41. Lombardino JG and Lowe JA. The Role of the Medicinal Chemist in Drug Discovery—Then and Now. Nat Rev Drug Discov 2004; 3: 853–862.PubMedCrossRefGoogle Scholar
  42. Lu J and Bakken GA. Building Classification Models for DMSO Solubility: Comparison of Five Methods. Abstracts of Papers, 228th ACS National Meeting, Philadelphia, PA, United States, August 22–26, 2004, CINF-045.Google Scholar
  43. McGovern SL, Caselli E, Grigorieff N, and Shoichet BK. A Common Mechanism Underlying Promiscuous Inhibitors from Virtual and High-Throughput Screening. J Med Chem 2002; 45: 1712–1722.PubMedCrossRefGoogle Scholar
  44. McGovern SL, Helfand BT, Feng B, and Shoichet BK. A Specific Mechanism of Nonspecific Inhibition. J Med Chem 2003; 46: 4265–4272.PubMedCrossRefGoogle Scholar
  45. McGovern SL and Shoichet BK. Kinase Inhibitors: Not Just for Kinases Anymore. J Med Chem 2003; 46: 1478–1483.PubMedCrossRefGoogle Scholar
  46. Meisner N-C, Hintersteiner M, Uhl V, Weidemann T, Schmied M, Gstach H, and Auer M. The Chemical Hunt for the Identification of Drugable Targets. Curr Opin Chem Biol 2004; 8: 424–431.PubMedCrossRefGoogle Scholar
  47. Miller KA, SureshKumar EVK, Wood SJ, Cromer JR, Datta A, and David SA. Lipopolysaccharide Sequestrants: Structural Correlates of Activity and Toxicity in Novel Acylhomospermines. J Med Chem 2005; 48: 2589–2599.PubMedCrossRefGoogle Scholar
  48. Moore K and Rees S. Cell-Based Versus Isolated Target Screening: How Lucky Do You Feel? J Biomol Screen 2001; 6: 69–74.PubMedGoogle Scholar
  49. Oldenburg K, Pooler D, Scudder K, Lipinski C, and Kelly M. High Throughput Sonication: Evaluation for Compound Solubilization. Comb Chem High Throughput Screen 2005; 8: 499–512.PubMedCrossRefGoogle Scholar
  50. Oprea TI, Bologa CG, Edwards BS, Prossnitz ER, and Sklar LA. Post-High-Throughput Screening Analysis: An Empirical Compound Prioritization Scheme. J Biomol Screen 2005; 10: 419–426.PubMedCrossRefGoogle Scholar
  51. Popa-Burke IG, Issakova O, Arroway JD, Bernasconi P, Chen M, Coudurier L, Galasinski S, Jadhav AP, Janzen WP, Lagasca D, Liu D, Lewis RS, Mohney RP, Sepetov N, Sparkman DA, and Hodge CN. Streamlined System for Purifying and Quantifying a Diverse Library of Compounds and the Effect of Compound Concentration Measurements on the Accurate Interpretation of Biological Assay Results. Anal Chem 2004; 76: 7278–7287.PubMedCrossRefGoogle Scholar
  52. Roche O, Schneider P, Zuegge J, Guba W, Kansy M, Alanine A, Bleicher K, Danel F, Gutknecht E-M, Rogers-Evans M, Neidhart W, Stalder H, Dillon M, Sjogren E, Fotouhi N, Gillespie P, Goodnow R, Harris W, Jones P, Taniguchi M, Tsujii S, von der Saal W, Zimmermann G, and Schneider G. Development of a Virtual Screening Method for Identification of “Frequent Hitters” in Compound Libraries. J Med Chem 2002; 45: 137–142.PubMedCrossRefGoogle Scholar
  53. Roehrl MHA, Wang JY, and Wagner G. Discovery of Small-Molecule Inhibitors of the NFAT-Calcineurin Interaction by Competitive High-Throughput Fluorescence Polarization Screening. Biochemistry 2004; 43: 16067–16075.PubMedCrossRefGoogle Scholar
  54. Ryan AJ, Gray NM, Lowe PN, and Chung C-W. Effect of Detergent on “Promiscuous” Inhibitors. J Med Chem 2003; 46: 3448–3451.PubMedCrossRefGoogle Scholar
  55. Schmidt M and Bornscheuer UT. High-throughput Assays for Lipases and Esterases. Biomol Eng 2005; 22: 51–56.PubMedCrossRefGoogle Scholar
  56. Schopfer U, Engeloch C, Stanek J, Girod M, Schuffenhauer A, Jacoby E, and Acklin P. The Novartis Compound Archive—From Concept to Reality. Comb Chem High Throughput Screen 2005; 8: 513–519.PubMedCrossRefGoogle Scholar
  57. Seidler J, McGovern SL, Doman TN, and Shoichet BK. Identification and Prediction of Promiscuous Aggregating Inhibitors among Known Drugs. J Med Chem 2003; 46: 4477–4486.PubMedCrossRefGoogle Scholar
  58. Topp A, Zbinden P, Wehner HU, and Regenass U. A Novel Storage and Retrieval Concept for Compound Collections on Dry Film. J Association for Laboratory Automation 2005; 10: 88–97.CrossRefGoogle Scholar
  59. Walters WP and Namchuk M. Designing Screens: How To Make Your Hits a Hit. Nat Rev Drug Discov 2003; 2: 259–266.PubMedCrossRefGoogle Scholar
  60. Yan B, Collins N, Wheatley J, Irving M, Leopold K, Chan C, Shornikov A, Fang L, Lee A, Stock M, and Zhao J. High-Throughput Purification of Combinatorial Libraries I: A High-Throughput Purification System Using an Accelerated Retention Window Approach. J Comb Chem 2004; 6: 255–261.PubMedCrossRefGoogle Scholar
  61. Yan B, Fang L, Irving M, Zhang S, Boldi AM, Woolard F, Johnson CR, Kshirsagar T, Figliozzi GM, Krueger CA, and Collins N. Quality Control in Combinatorial Chemistry: Determination of the Quantity, Purity, and Quantitative Purity of Compounds in Combinatorial Libraries. J Comb Chem 2003; 5: 547–559.PubMedCrossRefGoogle Scholar
  62. Yurek DA, Branch DL, and Kuo M-S. Development of a System To Evaluate Compound Identity, Purity, and Concentration in a Single Experiment and Its Application in Quality Assessment of Combinatorial Libraries and Screening Hits. J Comb Chem 2002; 4: 138–148.PubMedCrossRefGoogle Scholar

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© Springer 2007

Authors and Affiliations

  • LI DI
    • 1
    • 1
  1. 1.Wyeth ResearchPrinceton

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