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Discovery and Optimization of Lead Compounds

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Discovery of Lead Compounds

Hit to lead
Hit to Lead

The discovery of lead compounds is the process of turning the “hits” found in screening into “lead compounds” that can be further optimized. The lead compound may be a selected compound or a series of homologs, or it may be a compound derived from literature. However, for high-throughput screening, discrete, multiple series of emerging compounds may be produced, which requires selecting one of the series to continue research. This process is called “Hit to Lead”.

The “Hit to Lead” process should pay attention to:

Tightly combine specific biological activity and ADME properties
Parallel biological evaluation and “developability” evaluation are essential
Dense data matrix
High degree of automation, high level of calculation and analysis
Cycle length is the key to success, and in vitro ADME analysis and calculation tools need to be integrated
Calculation tools can play an important role
If you want to outsource successfully, you need CRO to obtain all chemical/biological/compound/ADME data

A good lead compound needs to meet:

  • From high-throughput screening to get ideal enough, multiple discrete series of compounds

  • Use fresh, high-purity samples to confirm biological activity and compound structure

  • In vitro activity <3μM, suitable functional activity

  • Reversibility

  • Feasible selective experiment

  • A single compound needs to synthesize a small compound library of the same series to confirm its activity

  • 5-10 compounds are needed to confirm the diversity of choices

  • No unnecessary functional groups or chemical reaction groups

  • No toxic group

  • Modifiable chemical sites

  • Traceable physical properties

  • Molecular weight, solubility, polarity

  • ADME properties that can be analyzed for representative homologs

  • Particular attention is paid to proper oral absorption properties, solubility for intravenous injection and permeability of the central nervous system

  • ADME issues are tractable

*Special attention: Biological activity is usually the easiest property to optimize.

Optimization of Lead Compounds

Hit to Lead Optimization
Hit to Lead Optimization

Lead compound optimization is the process of selecting a lead compound for preclinical evaluation and converting it into a candidate drug:

  • Most of the time is spent on solving ADME/T problems

  • Separate study of pharmacokinetics and pharmacodynamics duration of action can reap unexpected benefits

  • When modifying the lead compound, pay close attention to the changes in its physical and chemical properties

  • For compounds that are not selective, consider off-target effects/toxicity

  • Pay close attention to pre-clinical research requirements

  • The best way to gain experience is from actual work and reading drug development cases

Related Articles:

Hit Identification in Drug Discovery

Discovery of hit compounds

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