Deconstructing Markush: Improving the R&D Efficiency Using Library Selection in Early Drug Discovery

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Computational Chemistry

Background:

• Product patents frequently utilize Markush structures to claim numerous compounds.
• Traditional drug discovery often relies on the Free Wilson approach, focusing narrowly on chemical space near a known hit compound.

Purpose of the Study:

• To evaluate the effectiveness of rational compound selection versus conventional methods in representing the full chemical diversity within patent Markush structures.
• To assess the ability of different selection strategies to cover the chemical space defined by seven real-case patents.

Main Methods:

• Comparative analysis of rational selection techniques against conventional approaches.
• Application of methods to seven real-world patent case studies.
• Assessment of chemical space coverage for each approach.

Main Results:

• Conventional methods, such as the Free Wilson approach, often explore only a small region of the potential chemical space defined by Markush structures.
• Rational selection methods demonstrated a superior ability to sample and represent the broader molecular diversity present in patent claims.
• The study identified significant under-exploration of chemical space in typical patent analyses.

Conclusions:

• Conventional patent analysis methods may overlook diverse and potentially active compounds.
• Integrating computer-aided library selection early in drug discovery can significantly enhance the identification of novel drug candidates.
• Rational selection strategies are crucial for maximizing the exploration of chemical space in drug discovery programs.