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Is there a difference between leads and drugs? A historical perspective
T I Oprea1, A M Davis, S J Teague
1AstraZeneca R&D Mölndal, EST Lead Informatics, S 431 83 Mölndal, Sweden. Tudor.Oprea@astrazeneca.com
Journal of Chemical Information and Computer Sciences
|October 18, 2001
Summary
Drug discovery leads are less complex and hydrophobic than marketed drugs. Optimization increases molecular complexity, guiding the design of new combinatorial libraries for lead discovery.
Area of Science:
- Medicinal Chemistry
- Drug Discovery
- Computational Chemistry
Background:
- Lead structures require simple chemical features, established SAR, favorable patents, and good ADME properties for development.
- Leads can be novel structures or modified marketed drugs.
- Previous work analyzed 18 lead-drug pairs; this study expands to 96 pairs.
Observation:
- Analyzed properties include molecular weight (MW), refractivity (CMR), rings (RNG), rotatable bonds (RTB), hydrogen bond donors/acceptors (HDO/HAC), lipophilicity (CLogP, LogD(74)), and druglike scores (DFPS, PPFS).
- Compared medians revealed significant differences between leads and drugs across these properties.
- Leads generally exhibit lower MW, CMR, RNG, RTB, CLogP, LogD(74), DFPS, and PPFS compared to drugs.
Findings:
- Lead structures are less complex, with lower molecular weight, fewer rings, and fewer rotatable bonds.
- Leads are less hydrophobic, indicated by lower CLogP and LogD(74) values.
- Lead structures possess lower druglike scores (DFPS and PPFS) than marketed drugs.
Implications:
- The optimization process from a lead to a drug increases molecular complexity and potentially hydrophobicity.
- These quantitative differences inform the design of combinatorial libraries for more effective lead discovery.
- Understanding lead vs. drug properties aids in developing strategies for novel drug development.