Discovery of Innovative Drug Lead Compounds
FDA approved drugs only cover approximately 800 targets, but many of the known disease-related targets are “difficult to drug” or “undruggable”. These “difficult to drug” targets refer to treatment targets that are difficult to target with traditional methods but are clinically important. With the development of new technologies, targets such as SHP2 and KRAS, which are traditionally considered “difficult to drug”, are gradually being broken through, and even becoming the most popular targets today.
Initiating from large-scale small molecule libraries and employing various screening technology platforms to discovery lead compounds for protein targets of interest is one of the main strategies for “first-in-class” drug development. But at present, most drug screening techniques use pure proteins as experimental systems. The expression and purification process of target proteins involves multiple challenges, such as selecting appropriate expression systems, achieving high purity, and maintaining structural and functional integrity, especially for membrane protein-related targets. As a result, the initial purification and preparation of target proteins often become critical bottlenecks in the drug discovery industry.
The advent of chemoproteomics technology has revolutionized drug discovery, shifting it from pure protein system to live cell system. Taking the discovery of lead compound of covalent drug as an example, it begins with structurally diverse molecular libraries. Small molecules are applied at the cellular level to ensure that proteins are in their natural active state. Subsequently, with the aid of bio-active probes, activity-based protein profiling (ABPP) is utilized to capture and analyze the binding capability of each small molecule with target proteins, thereby constructing a network database of interaction between small molecules and proteins.
Technical Advantages
Why Choose ChemPro Innovations
Our chemoproteomics screening platform is capable of discovering lead compounds for almost all proteins in living cells, with precision to the level of drug binding pockets and amino acid residues, which improves efficiency while reducing risk, ensuring that every screening experiment yields results.
1.Structurally diverse drug-like molecule library
The molecules in this molecular library contain acrylamide, chloroacetamide and other reactive groups with mild electrophilic reactivity. Among them, the acrylamide reactive group is used by the vast majority of FDA-approved cysteine residue-targeted covalent drugs. In terms of molecular structure design, it conforms to Lipinski’s five rules for class drugs.
2.Covering new protein targets
At present, the protein target library captured by bio-active chemical probes covers 12421 proteins, 39962 cysteine binding sites, and is distributed in multiple protein target families with important biological functions, such as kinases, GPCRs, etc. A variety of popular clinical drug targets are covered, as well as a large number of new targets and new drug binding pockets, laying the foundation for the discovery of lead compounds with new mechanisms and new structures.
Workflow
1.Covalent molecular library screening
2.Cell incubation
3.Universal probe labeling
4.Bio-active chemical probe labeling
5.Mass spectrometry data analysis
6.Determination of target points and protein binding methods