Molecular properties that influence oral drug-like behavior

Current Opinion in Drug Discovery and Development

Volumn 7, Issue 4, 2004, Pages 470-477

  Lajiness, Michael S ^a   Vieth, Michal ^a   Erickson, Jon ^a  

^a ELI LILLY AND COMPANY   (United States)

Author keywords

Bioavailability; Bioavailability trends; Groups of compounds; Molecular properties; Oral drug likeness; Oral drugs; Predictions; Statistical analysis

Indexed keywords

BLOOD BRAIN BARRIER; CENTRAL NERVOUS SYSTEM; DRUG BIOAVAILABILITY; DRUG RESEARCH; PRACTICE GUIDELINE; PREDICTION; RELIABILITY; REVIEW; COMPARATIVE STUDY; CONFORMATION; DRUG DESIGN; DRUG INDUSTRY; METHODOLOGY; MOLECULAR WEIGHT; ORAL DRUG ADMINISTRATION; PHARMACEUTICS; SYNTHESIS;

DRUG;

ADMINISTRATION, ORAL; DRUG DESIGN; DRUG INDUSTRY; MOLECULAR CONFORMATION; MOLECULAR WEIGHT; PHARMACEUTICAL PREPARATIONS; TECHNOLOGY, PHARMACEUTICAL;

EID: 4644301831     PISSN: 13676733     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (36)

1. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ: Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev (2001) 46(1-3):3-25. This paper is the basis for Lipinski's ROF, which is widely used in the pharmaceutical industry, and contains a good discussion of solubility and permeability of known drugs. This classic paper should be considered required reading for anyone involved in drug discovery.
2. Lipinski CA: Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods (2000) 44(1):235-249.
3. Muegge I: Selection criteria for drug-like compounds. Med Res Rev (2003) 23(3):302-321. This review surveys computational techniques that are used to evaluate the drug-likeness of compound selections and offers an outlook for further development of the field.
4. Muegge I, Heald SL, Brittelli D: Simple selection criteria for drug-like chemical matter. J Med Chem (2001) 44(12):1841-1846.
5. Walters WP, Murcko MA: Prediction of 'drug-likeness'. Adv Drug Deliv Rev (2002) 54(3):255-271.
6. Walters WP, Ajay, Murcko MA: Recognizing molecules with drug-like properties. Curr Opin Chem Biol (1999) 3(4):384-387.
7. Ghose AK, Viswanadhan VN, Wendelowski JJ: A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J Comb Chem (1999) 1(1):55-67.
8. Oprea TI: Current trends in lead discovery: Are we looking for the appropriate properties? J Comput Aided Mol Des (2002) 16(5-6):325-334. A contribution to the debate on which kinds of compounds the pharmaceutical industry should be targeting, ie, drugs or leads. The range of molecular properties that describe leads are repeated in this paper.
9. Andrews PR, Craik DJ, Martin JL: Functional group contributions to drug-receptor interactions. J Med Chem (1984) 27(12):1648-1657.
10. Gillet VJ, Willett P, Bradshaw J: Identification of biological activity profiles using substructural analysis and genetic algorithms. J Chem Inf Comput Sci (1998) 38(2):165-179.
11. Xu J, Stevenson J: Drug-like index: A new approach to measure drug-like compounds and their diversity. J Chem Inf Comput Sci (2000) 40(5):1177-1187.
12. Bemis GW, Murcko MA: The properties of known drugs. 1. Molecular frameworks. J Med Chem (1996) 39(15):2887-2893.
13. Bemis GW, Murcko MA: Properties of known drugs. 2. Side chains. J Med Chem (1999) 42(25):5095-5099.
14. Wang J, Ramnarayan K: Towards designing drug-like libraries: A novel computational approach for prediction of drug feasibility of compounds. J Comb Chem (1999) 1(6):524-533.
15. Vieth M, Siegel MG, Higgs RE, Watson IA, Robertson DH, Savin KA, Durst GL, Hipskind PA: Characteristic physical properties and structural fragments of marketed oral drugs. J Med Chem (2004) 47(1):224-232. The molecular property means of oral drugs have not significantly changed over the last 20 years. In addition, the properties of oral drugs were demonstrated to be markedly different than those of injectable drugs.
16. Lewell XQ, Judd DB, Watson SP, Hann MM: RECAP - Retrosynthetic combinatorial analysis procedure: A powerful new technique for identifying privileged molecular fragments with useful applications in combinatorial chemistry. J Chem Inf Comput Sci (1998) 38(3):511-522.
17. Ajay A, Walters WP, Murcko MA: Can we learn to distinguish between "drug-like" and "nondrug-like" molecules? J Med Chem (1998) 41(18):3314-3324.
18. Sadowski J, Kubinyi H: A scoring scheme for discriminating between drugs and nondrugs. J Med Chem (1998) 41(18):3325-3329.
19. Wagener M, van Geerestein VJ: Potential drugs and nondrugs: Prediction and identification of important structural features. J Chem Inf Comput Sci (2000) 40(2):280-292.
20. Podlogar BL, Muegge I, Brice LJ: Computational methods to estimate drug development parameters. Curr Opin Drug Discovery Dev (2001) 4(1):102-109.
21. Kubinyi H: Drug research: Myths, hype and reality. Nat Rev Drug Disc (2003) 2(8):665-668.
22. Farmer PS, Ariens EJ: Speculations on the design of nonpeptidic peptidomimetics. Trends Pharm Sci (1982) 3:362-365.
23. Hann MM, Leach AR, 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. A contribution that highlights many of the differences between leads and drugs and demonstrates that an optimal complexity exists for typical drugs and leads.
24. Sneader W (Ed): Drug Prototypes and their Exploitation. John Wiley & Sons, New York, NY, USA (1996).
25. Wenlock MC, Austin RP, Barton P, Davis AM, Leeson PD: A comparison of physiochemical property profiles of development and marketed oral drugs. J Med Chem (2003) 46(7):1250-1256. One of the first papers that used simple statistical tests to detect property differences between various groups of clinical compounds. It was observed that the mean properties of development compounds converge toward the mean properties of marketed oral drugs. This is a reference that any reader interested in the molecular properties of drug-like compounds should consider.
26. Blake JF: Examination of the computed molecular properties of compounds selected for clinical development. BioTechniques (2003) 34:S16-S20.
27. Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD: Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem (2002) 45(12):2615-2623. Paper examining trends in the molecular properties of an internal set of GlaxoSmithKline compounds along with measured rat bioavailability and permeation data. This is essential reading for anyone interested in the association between PSA and bioavailability.
28. Palm K, Stenberg P, Luthman K, Artursson P: Polar molecular surface properties predict the intestinal absorption of drugs in humans. Pharm Res (1997) 14(5):568-571.
29. Clark DE: Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena. 2. Prediction of blood-brain barrier penetration. J Pharm Sci (1999) 88(8):815-821.
30. Takaoka Y, Endo Y, Yamanobe S, Kakinuma H, Okubo T, Shimazaki Y, Ota T, Sumiya S, Yoshikawa K: Development of a method for evaluating drug-likeness and ease of synthesis using a data set in which compounds are assigned scores based on chemists' intuition. J Chem Inf Comput Sci (2003) 43(4):1269-1275.
31. MDL Drug Data Report: MDL Information Systems Inc, San Leandro, CA, USA. http://www.mdl.com/products/knowledge/drug_data_report/index.jsp
32. MDL Comprehensive Medicinal Chemistry: MDL Information Systems Inc, San Leandro, CA, USA. http://www.mdl.com/products/knowledge/medicinal_chem/index.jsp
33. Derwent World Drug Index: Thomson Scientific, London, UK. http://www.derwent.com/products/lr/wdi/
34. MDL Available Chemicals Directory: MDL Information Systems Inc, San Leandro, CA, USA. http://www.mdl.com/products/experiment/available_chem_dir/ index.jsp
35. Rishton GM: Nonleadlikeness and leadlikeness in biochemical screening. Drug Disc Today (2003) 8(2):86-96.
36. Lewis RA, Mason JS, McLay IM: Similarity measures for rational set selection and analysis of combinatorial libraries: The diverse property-derived (DPD) approach. J Chem Inf Comput Sci (1997) 37(3):599-614.