Molecular Diversity

, Volume 5, Issue 4, pp 199-208

First online:

Current trends in lead discovery: Are we looking for the appropriate properties?

  • Tudor I. OpreaAffiliated withDept. Biochemistry and Molecular Biology and Office of Biocomputing, UNM School of Medicine

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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 [17])and LogSw (intrinsic water solubility, estimated by Wskowwin [18])for the following categories: 62 leads and 75 drugs [11];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.

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