Heat shock protein 90 (Hsp90) is an essential molecular chaperone involved in the folding, stabilization, and activation of numerous client proteins. Many of these client proteins are key players in cancer pathways, making Hsp90 an attractive target for cancer therapeutics. The development and utilization of Hsp90-targeted libraries have opened new avenues in drug discovery. In this blog, we explore the strategic aspects of inhibitor design within the Hsp90-targeted library and its potential in revolutionizing cancer therapeutics.
Strategy of Inhibitor Design in Hsp90-Targeted Library:
Scaffold Exploration:
Designing inhibitors in the Hsp90-targeted library requires exploring diverse molecular scaffolds. Ranging from natural products to synthetic compounds, these scaffolds capture a wide range of chemical diversity. Through rational design and high-throughput screening, researchers can identify scaffolds with optimal binding affinity, selectivity, and pharmacokinetic properties. Scaffold exploration enables the design of potent inhibitors capable of disrupting the Hsp90-client protein interactions critical for tumor cell survival and growth.
Exploiting the ATP Binding Pocket:
The ATP binding pocket in the N-terminal domain of Hsp90 is a captivating target for inhibitor design. By exploiting this pocket, researchers can develop ATP-competitive inhibitors that competitively bind to Hsp90, thereby interfering with ATP-dependent conformational changes required for client protein maturation. Rational design, virtual screening, and structural insights play a significant role in identifying or modifying existing inhibitors to optimize their interaction with the ATP binding pocket, enhancing affinity and specificity.
Allosteric Modulation:
In addition to the ATP binding site, allosteric sites on Hsp90 present alternative opportunities for inhibitor design. Allosteric modulators can induce conformational changes that disrupt Hsp90 function and client protein binding. By targeting these sites, researchers can develop allosteric inhibitors that interfere with protein-protein interactions, leading to the degradation of client proteins or disruption of downstream signaling pathways. This strategic approach broadens the repertoire of inhibitor design within the Hsp90-targeted library.
Co-Chaperone Interactions:
Hsp90 interacts with various co-chaperones that assist in the folding and maturation of client proteins. Inhibitor design within the Hsp90-targeted library can focus on targeting specific co-chaperones that are critical for client protein stabilization or activation. By disrupting these co-chaperone interactions, researchers can selectively inhibit Hsp90 function in cancer cells, thereby affecting the stability of client proteins involved in oncogenic pathways. This targeted approach allows for the development of inhibitors that interfere with specific protein-protein interactions, offering potential for improved therapeutic outcomes.
Structure-Activity Relationship (SAR) Exploration:
The Hsp90-targeted library provides a platform to explore structure-activity relationships (SAR) and iteratively improve inhibitor design. By systematically modifying the chemical structure of initial hit compounds, researchers can optimize their properties to enhance potency, selectivity, and drug-like attributes. SAR exploration within the library allows for the identification of lead compounds with improved pharmacokinetic profiles, reduced toxicity, and enhanced efficacy, paving the way for drug candidates with high potential for clinical translation.
