Experimental validation of a fragment library for lead discovery using SPR biosensor technology

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Drug Discovery

Background:

• Fragment-based drug discovery (FBDD) is a key strategy for identifying novel drug leads.
• Developing robust fragment libraries is crucial for efficient screening.
• Surface Plasmon Resonance (SPR) biosensors offer sensitive detection of molecular interactions.

Purpose of the Study:

• To design and validate a new fragment library for SPR biosensor-based screening.
• To assess the suitability of the library for lead discovery against multiple drug targets.
• To evaluate the specificity and promiscuity of library compounds.

Main Methods:

• Selection of 930 compounds from over 4.6 million commercial compounds using physicochemical and medicinal chemistry filters.
• Screening of the library against three drug targets (HIV-1 protease, thrombin, carbonic anhydrase) and one non-target (human serum albumin) using SPR.
• Analysis of compound solubility and interaction profiles, including promiscuity and dissociation rates.

Main Results:

• High hit rates (35%-97%) were observed across different target proteins due to the high sensitivity of SPR.
• No promiscuous compounds (stoichiometry ≥5:1 with all 4 proteins) were identified.
• Only two compounds showed slow dissociation from all four proteins, indicating good specificity.
• Using multiple targets effectively identified and excluded potentially promiscuous compounds.

Conclusions:

• The designed fragment library is well-suited for SPR biosensor-based screening.
• The library demonstrates high specificity and low promiscuity, making it valuable for lead discovery.
• The experimental validation confirms the library's utility in identifying potential drug candidates.