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Current trends in lead discovery: are we looking for the appropriate properties?
1Dept. Biochemistry and Molecular Biology and Office of Biocomputing, UNM School of Medicine, 915 Camino de Salud NE, Albuquerque, NM 87131-5166, USA.
Journal of Computer-Aided Molecular Design
|December 20, 2002
Summary
Drug discovery prioritizes quality leads due to low success rates. Optimal leads are smaller, less hydrophobic, and more soluble than highly active compounds, guiding better lead selection.
Area of Science:
- Medicinal Chemistry
- Drug Discovery
- Computational Chemistry
Background:
- High-throughput screening (HTS) has shifted drug discovery focus from candidate drugs to quality leads.
- The probability of a drug progressing from HTS hit to market is extremely low (1 in a million).
Purpose of the Study:
- To analyze trends in lead discovery by comparing physicochemical properties (molecular weight, LogP, LogSw) of leads, drugs, and active compounds.
- To identify optimal physicochemical property profiles for successful drug development.
Main Methods:
- Comparison of molecular weight (MW), octanol/water partition coefficient (LogP), and intrinsic water solubility (LogSw) for 62 leads and 75 drugs.
- Analysis of compounds in development phases (I, II, III, launched) from the MDDR database.
- Evaluation of compounds from medicinal chemistry journals based on biological activity.
Main Results:
- Leads exhibit lower median MW and LogP, and higher median LogSw compared to marketed drugs and highly active compounds.
- Over 50% of active compounds (>1 nM) are larger, more hydrophobic, and less soluble than quality leads.
- Compounds in later development phases (I-III, launched) show progressive trends towards reduced MW/LogP and increased LogSw.
Conclusions:
- Physicochemical properties like solubility and hydrophobicity are critical for lead selection, beyond just binding affinity.
- Optimizing leads for favorable MW, LogP, and LogSw profiles enhances the probability of successful drug development.
- Current trends suggest a need to re-evaluate lead optimization strategies to incorporate these crucial properties earlier in the discovery pipeline.