Rational Method for Structural Simplification as Key Step in Hit Discovery: The Case of FGFR2 and IGF1R Dual...

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Computational Chemistry

Background:

• Traditional hit discovery involves filtering vast virtual libraries, often yielding complex molecules that are difficult to synthesize and may over-extrapolate predictive models.
• Selecting representative and promising compounds from millions of molecules presents a significant challenge in drug discovery.
• Overly complex molecular structures can hinder the practical application and efficiency of hit discovery processes.

Purpose of the Study:

• To develop a rational method for reducing the structural complexity of molecular candidates.
• To ensure that reduced structural complexity does not compromise biological activity.
• To improve the attainability and efficiency of the hit discovery process in medicinal chemistry.

Main Methods:

• A rational-based approach was employed to systematically reduce the structural complexity of molecular candidates.
• The method focused on maintaining or improving biological activity while simplifying molecular structures.
• The approach was applied to identify dual inhibitors for specific tyrosine kinases.

Main Results:

• The developed method successfully reduced the structural complexity of molecular candidates.
• The simplified molecules retained their biological activity, demonstrating the method's efficacy.
• The approach facilitated the identification of potential dual inhibitors targeting Fibroblast Growth Factor Receptor 2 (FGFR2) and Insulin-Like Growth Factor 1 Receptor (IGF1R).

Conclusions:

• The rational-based method offers an efficient strategy to simplify molecular structures in drug discovery.
• This approach enhances the attainability of drug candidates without sacrificing biological efficacy.
• The identified dual inhibitors for FGFR2 and IGF1R show promise for treating cancers like pancreatic ductal adenocarcinoma (PDAC).