Generating Multibillion Chemical Space of Readily Accessible Screening Compounds

Area of Science:

• Medicinal Chemistry
• Synthetic Chemistry
• Computational Chemistry

Background:

• Generating large chemical libraries is crucial for drug discovery.
• Traditional methods often face limitations in scale and accessibility.
• Readily accessible chemical libraries offer a strategic advantage in screening.

Purpose of the Study:

• To describe an efficient approach for generating ultra-large chemical libraries.
• To demonstrate the creation of a library exceeding 29 billion compounds.
• To analyze the drug-like and lead-like properties of the generated chemical space.

Main Methods:

• Utilizing two- or three-step, three-component reaction sequences.
• Employing readily available starting materials with validated reactivity.
• Selecting high-success-rate reactions (e.g., acylation-deprotection-acylation, amide formation-click chemistry).

Main Results:

• A chemical library of nearly 29 billion compounds was generated using two specific reaction sequences.
• The library contains substantial fractions of drug-like and "beyond rule-of-five" compounds.
• Over 22 million compounds met the stringent Churcher's rules for lead-likeness.

Conclusions:

• The described approach enables the efficient generation of ultra-large, diverse chemical libraries.
• The REAL (Readily Accessible) compounds library offers significant potential for drug discovery efforts.
• The library's composition supports exploration of both established and novel chemical spaces for therapeutic targets.