Current trends in lead discovery: Are we looking for the appropriate properties?
- Tudor I. Oprea
- … show all 1 hide
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
The new drug discovery paradigm is based on high-throughputtechnologies, both with respect to synthesis and screening. Theprogression HTS hits → lead series → candidatedrug → marketed drugappears to indicate that the probability of reaching launched status isone in a million. This has shifted the focus from good qualitycandidate drugs to good quality leads. We examined the current trendsin lead discovery by comparing MW (molecular weight), LogP(octanol/water partition coefficient, estimated by Kowwin )and LogSw (intrinsic water solubility, estimated by Wskowwin )for the following categories: 62 leads and 75 drugs ;compounds in the development phase (I, II, III and launched), asindexed in MDDR; and compounds indexed in medicinal chemistry journals[ref. 20], categorized according to their biological activity.Comparing the distribution of the above properties, the 62 leadstructures show the lowest median with respect to MW (smaller) and LogP(less hydrophobic), and the highest median with respect to LogSw (moresoluble). By contrast, over 50% of the medicinal chemistry compoundswith activities above 1 nanomolar have MW > 425, LogP > 4.25 andLogSw < -4.75, indicating that the reported active compounds arelarger, more hydrophobic and less soluble when compared to time-testedquality leads. In the MDDR set, a progressive constraint to reduce MWand LogP, and to increase LogSw, can be observed when examining trendsin the developmental sequence: phase I, II, III and launched drugs.These trends indicate that other properties besides binding affinity,e.g., solubility and hydrophobicity, need to be considered whenchoosing the appropriate leads.
- Drews, J., Drug Discov. Today, 3 (1998) 491–494.
- Horrobin, D.F., J. R. Soc. Med., 93 (2000) 341–345.
- Olsson, T. and Oprea, T.I. Curr. Op Drug Discov. Dev., 4 (2001) 308–313.
- Lebl, M., J. Comb. Chem., 1 (1999) 3–24.
- Martin, Y.C., J. Comb. Chem. 3 (2001) 231–250.
- Fox, S., Farr-Jones, S. and Yund, M.A., J. Biomol. Screening, 4 (1999) 183–186.
- Oprea, T.I., Curr. Op. Chem. Biol., 6 (2002) 384–389.
- Rishton, G.M., Drug Discov. Today, 2 (1997) 382–384.
- DeStevens, G., Prog. Drug. Res., 30 (1986) 189–203.
- Oprea, T.I., Davis, A.M., Teague, S.J. and Leeson, P.D., J. Chem. Inf. Comput. Sci., 41 (2001) 1308–1315.
- Boyd, D.B., In: Liljefors, T., Jorgensen, F.S., Krogsgaard-Larsen, P. (eds.) Rational Molecular Design in Drug Research, Munksgaard, Copenhagen, (1998) 15–29.
- Kennedy, T., Drug Discov. Today, 2 (1997) 436–444.
- Lipinski, C.A., Lombardo, F., Dominy, B.W. and Feeney, P.J., Adv. Drug. Deliv. Rev., 23 (1997) 3–25.
- Teague, S.J., Davis, A.M., Leeson, P.D. and Oprea, T.I., Angew. Chem. Int. Ed., 38 (1999) 3743–3748. German version: Angew. Chem., 111 (1999) 3962-3967.
- Hann, M.M., Leach, A.R. and Harper, G., J. Chem. Inf. Comput. Sci., 41 (2001) 856–864.
- Meylan, W.M. and Howard, P.H., J. Pharm. Sci., 84 (1995) 83–92. KOWWIN v1.6 is available from US EPA, http://www.epa.gov/oppt/exposure/docs/episuited1.htm
- Meylan, W.M., Howard, P.H. and Boethling, R.S., Environ. Toxicol. Chem., 15 (1996) 100–106. WSKOWIN 1.40 is available from US EPA, http://www.epa.gov/oppt/ exposure/docs/episuited1.htm
- The following publications were included in this survey: Journal of Medicinal Chemistry volumes 40 (1997) and 41 (1998) - forming over 90% of the structures analysed; Quantitative Structure Activity Relationships volumes 17 (1998), 18 (1999), and 19 (2000), as well as European Journal of Medicinal Chemistry volume 36 (2001).
- Lipinski, C.A., J. Pharmacol Toxicol Meth., 44 (2000) 235–249.
- Kuntz, I.D., Chen, K., Sharp, K.A. and Kollman, P.A., Proc. Natl. Acad. Sci. USA, 96 (1999) 9997–10002.
- Oprea, T.I., Molecules, 7 (2002) 55-64.
- Current trends in lead discovery: Are we looking for the appropriate properties?
Volume 5, Issue 4 , pp 199-208
- Cover Date
- Print ISSN
- Online ISSN
- Kluwer Academic Publishers
- Additional Links
- database filtering
- drug research
- property distribution
- `rule of 5' test
- Industry Sectors
- Tudor I. Oprea (1)
- Author Affiliations
- 1. Dept. Biochemistry and Molecular Biology and Office of Biocomputing, UNM School of Medicine, 915 Camino de Salud NE, Albuquerque, NM, 87131-5166, USA