The Proximal Lilly Collection: Mapping, Exploring and Exploiting Feasible Chemical Space

Area of Science:

• Medicinal Chemistry
• Chemoinformatics
• Drug Discovery

Background:

• Exploring vast chemical space for novel small molecules is crucial but challenging.
• Synthesizability of in silico-designed compounds remains a practical obstacle.
• Existing methods often struggle with the sheer number of theoretically possible compounds.

Purpose of the Study:

• To define and provide access to a virtual collection of synthesizable, drug-like small molecules.
• To leverage in-house synthetic knowledge and resources for drug discovery.
• To facilitate exploration of feasible chemical space for identifying novel therapeutics.

Main Methods:

• Implementation of the Proximal Lilly Collection (PLC) initiative.
• Coupling synthetic knowledge with chemo/reaction informatics tools.
• Development of a computational framework for managing a virtual compound collection.

Main Results:

• Creation of a large, realistically feasible virtual collection of drug-like compounds.
• Demonstration of the PLC's utility through the discovery of selective kinase inhibitors.
• Facilitation of drug discovery research by providing accessible virtual compound libraries.

Conclusions:

• The PLC initiative successfully addresses the challenge of synthesizability in virtual screening.
• Accessible, feasible virtual collections significantly enhance drug discovery efforts.
• This approach enables the identification of novel drug candidates, exemplified by kinase inhibitors.