Rule of five in 2015 and beyond: Target and ligand structural limitations, ligand chemistry structure and drug discovery project decisions

Advanced Drug Delivery Reviews

Volumn 101, Issue , 2016, Pages 34-41

  Lipinski, Christopher A ^a  

^a NONE   (United States)

Author keywords

Binding pockets in folded proteins; Biologically active chemistry space; Characteristics of protein ligands; H bonding in natural products; Natural product chemistry synthons; Navitoclax a rule of 5 outlier; Protein binding pocket evolution; Shape change in natural products

Indexed keywords

BINS; BIOCHEMISTRY; CHELATION; CHEMICAL BONDS; DRUG PRODUCTS; HYDROGEN BONDS; LIGANDS; ONTOLOGY; PRODUCT DESIGN; PROTEINS; STATISTICS; STRUCTURAL DESIGN; STRUCTURE (COMPOSITION);

BIOLOGICALLY ACTIVE CHEMISTRY SPACE; FOLDED PROTEINS; NATURAL PRODUCTS; NAVITOCLAX A RULE OF 5 OUTLIER; PROTEIN BINDING; PROTEIN LIGANDS; SYNTHONS;

BINDING SITES;

CYCLOSPORIN A; LIGAND; NATURAL PRODUCT; NAVITOCLAX; ANILINE DERIVATIVE; BIOLOGICAL PRODUCT; CYCLOSPORINE; DRUG; SULFONAMIDE;

AREA UNDER THE CURVE; BIOSYNTHESIS; CHEMICAL INTERACTION; DECISION MAKING; DRUG ABSORPTION; DRUG BINDING SITE; DRUG STRUCTURE; HUMAN; HYDROGEN BOND; MEDICINAL CHEMISTRY; PHARMACOLOGICAL PARAMETERS; PHYSICAL CHEMISTRY; PRIORITY JOURNAL; PROTEIN FOLDING; REVIEW; RULE OF FIVE; CHEMISTRY; DRUG DEVELOPMENT;

ANILINE COMPOUNDS; BIOLOGICAL PRODUCTS; CYCLOSPORINE; DRUG DISCOVERY; HUMANS; HYDROGEN BONDING; LIGANDS; PHARMACEUTICAL PREPARATIONS; SULFONAMIDES;

EID: 84966707674     PISSN: 0169409X     EISSN: 18728294     Source Type: Journal    
DOI: 10.1016/j.addr.2016.04.029     Document Type: Review

References (57)

1. [1] Lipinski, C.A., Lombardo, F., Dominy, B.W., Feeney, P.J., Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 23 (1997), 3–25.
2. [2] Lipinski, C., Hopkins, A., Navigating chemical space for biology and medicine. Nature 432 (2004), 855–861.
3. [3] Weskamp, N., Hüllermeier, E., Klebe, G., Merging chemical and biological space: structural mapping of enzyme binding pocket space. Proteins: Struct., Funct., Bioinf. 76 (2009), 317–330.
4. [4] Barelier, S., Sterling, T., O'Meara, M.J., Shoichet, B.K., The recognition of identical ligands by unrelated proteins. ACS Chem. Biol. 10 (2015), 2772–2784.
5. [5] Hert, J., Keiser, M.J., Irwin, J.J., Oprea, T.I., Shoichet, B.K., Quantifying the relationships among drug classes. J. Chem. Inf. Model. 48 (2008), 755–765.
6. [6] Axe, D.D., Estimating the prevalence of protein sequences adopting functional enzyme folds. J. Mol. Biol. 341 (2004), 1295–1315.
7. [7] Dobson, C.M., Chemical space and biology. Nature 432 (2004), 824–828.
8. [8] Triggle, D.J., The chemist as astronaut: searching for biologically useful space in the chemical universe. Biochem. Pharmacol. 78 (2009), 217–223.
9. [9] Anonymous, Growth of unique folds per year as defined by SCOP (v1.75), Protein Data Bank, http://www.rcsb.org/pdb/statistics/contentGrowthChart.do?content=fold-scop.
10. [10] Sikosek, T., Chan, H.S., Biophysics of protein evolution and evolutionary protein biophysics. J. R. Soc. Interface, 11, 2014, 20140419.
11. [11] Weisel, M., Proschak, E., Kriegl, J.M., Schneider, G., Form follows function: shape analysis of protein cavities for receptor-based drug design. Proteomics 9 (2009), 451–459.
12. [12] Abagyan, R., Ricci, C.G., Schneider, Gisbert, (eds.) The Human Pocketome, De Novo Molecular Design, first ed., 2014, Wiley-VCH, 73–96 (Chapter 3).
13. [13] Perola, E., Charifson, P.S., Conformational analysis of drug-like molecules bound to proteins: an extensive study of ligand reorganization upon binding. J. Med. Chem. 47 (2004), 2499–2510.
14. [14] Bartolowits, M., V. Davisson, Considerations of protein subpockets in fragment-based drug design. Chem. Biol. Drug Des. 87 (2016), 5–20.
15. [15] Binding of small molecules to cavity forming mutants of a de novo designed protein, A. Das, Y. Wei, I. Pelczer, M.H. Hecht. Protein Sci., 20, 2011, 702–711.
16. [16] Patel, S.C., Bradley, L.H., Jinadasa, S.P., Hecht, M.H., Cofactor binding and enzymatic activity in an unevolved superfamily of de novo designed 4-helix bundle proteins. Protein Sci. 18 (2009), 1388–1400.
17. [17] Skolnick, J., Gao, M., Interplay of physics and evolution in the likely origin of protein biochemical function. PNAS 110 (2013), 9344–9349.
18. [18] Zauhar, R.J., Gianti, E., Welsh, W.J., Fragment-based shape signatures: a new tool for virtual screening and drug discovery. J. Comput. Aided Mol. Des. 27 (2013), 1009–1036.
19. [19] Cramer, R.D., Jilek, R.J., Guessregen, S., Clark, S.J., Wendt, B., Clark, R.D., “Lead hopping”. Validation of topomer similarity as a superior predictor of similar biological activities. J. Med. Chem. 47 (2004), 6777–6791.
20. [20] Gershenson, A., Gierasch, L.M., Pastore, A., Radford, S.E., Energy landscapes of functional proteins are inherently risky. Nat. Chem. Biol. 10 (2014), 884–891.
21. [21] Fitzpatrick, A.W., Knowles, T.P., Waudby, C.A., Vendruscolo, M., Dobson, C.M., Inversion of the balance between hydrophobic and hydrogen bonding interactions in protein folding and aggregation. PLoS Comput. Biol., 7, 2011, 1002169.
22. [22] Pérot, S., Sperandio, O., Miteva, M.A., Camproux, A., Villoutreix, B.O., Druggable pockets and binding site centric chemical space: a paradigm shift in drug discovery. Drug Discov. Today 15 (2010), 656–667.
23. [23] Wei, G., Xi, W., Nussinov, R., Ma, B., Protein ensembles: how does nature harness thermodynamic fluctuations for life? The diverse functional roles of conformational ensembles in the cell. Chem. Rev., 2010, 10.1021/acs.chemrev.5b00562.
24. [24] Andrec, M., Snyder, D.A., Zhou, Z., Young, J., Montelione, G.T., Levy, R.M., A large data set comparison of protein structures determined by crystallography and NMR: statistical test for structural differences and the effect of crystal packing. Proteins: Struct., Funct., Bioinf. 69 (2007), 449–465.
25. [25] Ferenczy, G.G., Keseru, G.M., On the enthalpic preference of fragment binding. Med. Chem. Commun. 7 (2016), 332–337.
26. [26] Kawasaki, Y., Chufan, E., LaFont, V., Hidaka, K., Kiso, Y., Mario Amzel, L., Freire, E., How much binding affinity can be gained by filling a cavity?. Chem. Biol. Drug Des. 75 (2010), 143–151.
27. [27] Freire, E., Waksman, (eds.) A Thermodynamic Guide to Affinity Optimization of Drug Candidates, Proteomics and Protein–Protein Interactions: Biology, Chemistry, Bioinformatics, and Drug Design, 2005, Springer, New York, 291–307 (Chapter 13).
28. [28] Böstrom, J., Brown, D., Stuck in a rut with old chemistry. Drug Discov. Today, 2016, 10.1016/j.drugdis.2016.02.017.
29. [29] Dewick, P.M., Secondary Metabolism: the Building Blocks and Construction Mechanisms, Medicinal Natural Products: a Biosynthetic Approach. 2001, John Wiley & Sons, Ltd, 7–34 (ISBNs: 0471496405 (hardback); 0471496413 (paperback); 0470846275 (electronic)).
30. [30] Lipinski, C.A., Litterman, N.K., Southan, C., Williams, A.J., Clark, A.M., Ekins, S., Parallel worlds of public and commercial bioactive chemistry data. J. Med. Chem. 58 (2015), 2068–2076.
31. [31] Müller, G., Giera, H., Protein secondary structure templates derived from bioactive natural products—combinatorial chemistry meets structure-based design. J. Comput. Aided Mol. Des. 12 (1998), 1–6.
32. [32] Hahk-Soo Kang, S.F., Brady, mining soil metagenomes to better understand the evolution of natural product structural diversity: pentangular polyphenols as a case study. J. Am. Chem. Soc. 136 (2014), 18111–18119.
33. [33] McArdle, B.M., Campitelli, M.R., Quinn, R.J., A common protein fold topology shared by flavonoid biosynthetic enzymes and therapeutic targets. J. Nat. Prod. 69 (2006), 14–17.
34. [34] Sturm, N., Quinn, R.J., Kellenberger, E., Similarity between flavonoid biosynthetic enzymes and flavonoid protein targets captured by three-dimensional computing approach. Planta Med. 81 (2015), 467–473.
35. [35] Koch, M.A., Schuffenhauer, A., Scheck, M., Wetzel, S., Casaulta, M., Odermatt, A., Ertl, P., Waldmann, H., Charting biologically relevant chemical space: a structural classification of natural products (SCONP). Proc. Natl. Acad. Sci. U. S. A. 102 (2005), 17272–17277.
36. [36] Grabowski, K., Schneider, G., Properties and architecture of drugs and natural products revisited. Curr. Chem. Biol., 1, 2007, 115-12.
37. [37] Doak, B.C., Zheng, J., Dobritzsch, D., Kihlberg, J., How beyond rule of 5 drugs and clinical candidates bind to their targets. J. Med. Chem. 59 (2016), 2312–2327.
38. [38] Bisson, J., McAlpine, J.B., Friesen, J.B., Chen, S., Graham, J., Pauli, G.F., Can invalid bioactives undermine natural product-based drug discovery?. J. Med. Chem., 2015 Oct 27 (epub ahead of print).
39. [39] Dancˇi'k, G.V., Seiler, K.P., Young, D.W., Schreiber, S.L., Clemons, P.A., Distinct biological network properties between the targets of natural products and disease. J. Am. Chem. Soc. 132 (2010), 9259–9261.
40. [40] Csermely, P., Korcsmáros, T., Kiss, H.J., London, G., Nussinov, R., Structure and dynamics of molecular networks: a novel paradigm of drug discovery a comprehensive review. Pharmacol. Ther. 138 (2013), 333–408.
41. [41] Camp, D., Garavelas, A., Campitelli, M., Analysis of physicochemical properties for drugs of natural origin. J. Nat. Prod. 78 (2015), 1370–1382.
42. [42] Driggers, E.M., Hale, S.P., Lee, J., Terrett, N.K., The exploration of macrocycles for drug discovery—an underexploited structural class. Nat. Rev. Drug Discov. 7 (2008), 608–624.
43. [43] Young-kwon, Kim, Dean, E.F. III, Arai, M.A., Arai, T., Patterson, N., Lamenzo, J.O., Clemons, P.A., Schreiber, S.L., Relationship of Stereochemical and skeletal diversity of small molecules to cellular measurement space. J. Am. Chem. Soc. 126 (2004), 14740–14745.
44. [44] El Tayar, N., Mark, A.E., Vallat, P., Brunne, R.M., Testa, B., van Gunsteren, W.F., Solvent-dependent conformation and hydrogen-bonding capacity of cyclosporin a: evidence from partition coefficients and molecular dynamics simulations. J. Med. Chem. 36 (1993), 3757–3764.
45. [45] Alex, A., Millan, D.S., Perez, M., Wakenhut, F., Whitlock, G.A., Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space. Med. Chem. Commun. 2 (2011), 669–674.
46. [46] Nicholls, I.A., Karlsson, B.C.G., Rosengren, A.M., Henschel, H., Warfarin: an environment-dependent switchable molecular probe. J. Mol. Recognit. 23 (2010), 604–608.
47. [47] Arkin, M.R., Tang, Y., Wells, J.A., Small-molecule inhibitors of protein–protein interactions: progressing toward the reality. Chem. Biol. 21 (2014), 1102–1114.
48. [48] Kuenemann, M.A., Bourbon, L.M., Labbé, C.M., Villoutreix, B.O., Sperandio, O., Which 3D characteristics make an efficient inhibitor of protein–protein interactions?. J. Chem. Inf. Model. 54 (2014), 3067–3079.
49. [49] Hann, M.M., Molecular obesity, potency and other addictions in drug discovery. Med. Chem. Commun. 2 (2011), 349–355.
50. [50] Franzini, R.M., Neri, D., Scheuermann, J., DNA-encoded chemical libraries: advancing beyond conventional small-molecule libraries. Acc. Chem. Res. 47 (2014), 1247–1255.
51. [51] Villoutreix, B.O., Labbé, C., Lagorce, D., Laconde, G., Sperandio, O., A leap into the chemical space of protein–protein interaction inhibitors. Curr. Pharm. Des., 30, 2012, 4648.
52. [52] Johnson, D.K., Karanicolas, J., Druggable protein interaction sites are more predisposed to surface pocket formation than the rest of the protein surface. PLoS Comput. Biol., 9(3), 2013, e1002951, 10.1371/journal.pcbi.1002951.
53. [53] Wendt, M.D., The discovery of navitoclax, a Bcl-2 family inhibitor, protein–protein interactions. Topics Med. Chem. 8 (2012), 231–258.
54. [54] Choo, E.F., Boggs, J., Zhu, C., Lubach, J.W., Catron, N.D., Jenkins, G., Souers, A.J., Voorman, R., The role of lymphatic transport on the systemic bioavailability of the Bcl-2 protein family inhibitors navitoclax (ABT-263) and ABT-199. Drug Metab. Dispos. 42 (2014), 207–212.
55. [55] Cheol-Min, Park, Bruncko, M., Adickes, J., Bauch, J., Ding, H., Kunzer, A., Marsh, K.C., Nimmer, P., Shoemaker, A.R., Song, X., Tahir, S.K., Tse, C., Wang, X., Wendt, M.D., Yang, X., Zhang, H., Fesik, S.W., Rosenberg, S.H., Elmore, S.W., Discovery of an orally bioavailable small molecule inhibitor of prosurvival B-cell lymphoma 2 proteins. J. Med. Chem. 51 (2008), 6902–6915.
56. [56] Meanwell, N.A., Watkins, W.J., Introduction to hepatitis C virus (HCV) therapies special thematic issue. J. Med. Chem. 57 (2014), 1625–1626.
57. [57] Belema, M., Meanwell, N.A., Discovery of daclatasvir, a pan-genotypic hepatitis C virus NS5A replication complex inhibitor with potent clinical effect. J. Med. Chem. 57 (2014), 5057–5071.