Assessing molecular scaffolds for CNS drug discovery

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Computational Chemistry

Background:

• High-quality screening collections are crucial for efficient drug discovery, maximizing hit rates and minimizing lead optimization time.
• Developing drug candidates for central nervous system (CNS) disorders presents unique challenges, particularly the need for compounds to cross the blood-brain barrier.
• Identifying and synthesizing molecules with desired properties for CNS drug discovery is a significant hurdle.

Purpose of the Study:

• To demonstrate the utility of a multiparameter optimization (MPO) tool for prioritizing molecular scaffold synthesis.
• To guide the generation of screening compounds with properties suitable for CNS lead generation.
• To facilitate the development of novel synthetic strategies for accessing CNS-relevant chemical space.

Main Methods:

• Utilized a multiparameter optimization (MPO) tool to score and prioritize molecular scaffolds.
• Employed computational methods to predict and optimize properties relevant to CNS drug discovery.
• Synthesized and experimentally validated decorated molecular scaffolds to assess their lead-like properties.

Main Results:

• The MPO tool successfully prioritized molecular scaffolds leading to screening compounds with experimentally validated CNS-relevant properties.
• The developed compounds exhibited characteristics aligned with the requirements for CNS lead generation.
• The study validated the effectiveness of the MPO approach in generating targeted chemical matter.

Conclusions:

• A multiparameter optimization (MPO) protocol can effectively guide the prioritization of molecular scaffolds for CNS drug discovery.
• This approach accelerates the identification of lead-like compounds with desirable blood-brain barrier permeability.
• Prospective application of this CNS Lead MPO scoring protocol can advance the synthesis of novel CNS-relevant chemical space.