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Drug Discovery: Overview

Drug Discovery: Overview

Drug discovery is a multifaceted process involving extensive screening, testing, and optimization of lead compounds to identify potential new drugs for therapeutic use. It combines several approaches, including screening large numbers of natural products, chemical modification of known active molecules, identification of new drug targets, and rational design based on biological mechanisms and drug-receptor structure. These approaches are carried out in both academic research laboratories and...

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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

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A Hit Prioritization Strategy for Compound Library Screening Using LiP-MS and Molecular Dynamics Simulations Applied

Foroughsadat Absar¹, Brandon Novy², Edith Nagy³

¹Segal Cancer Proteomics Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec H3T 1E2, Canada.

Analytical Chemistry

|September 12, 2025

Summary

This summary is machine-generated.

Limited proteolysis combined with mass spectrometry (LiP-MS) and molecular dynamics (MD) can identify KRas G12D inhibitors. This LiP-MS-MD approach aids in prioritizing drug discovery hits by revealing drug-target interactions.

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Area of Science:

Biochemistry
Structural Biology
Drug Discovery

Background:

Hit prioritization is crucial in drug discovery to eliminate false positives.
Orthogonal assays are needed to enhance sensitivity and accelerate the hit-to-lead process.
Limited proteolysis combined with mass spectrometry (LiP-MS) probes protein structure changes upon ligand binding.

Purpose of the Study:

To characterize small-molecule inhibitor interactions with the KRas G12D mutant oncoprotein.
To evaluate the utility of LiP-MS combined with molecular dynamics (MD) for hit validation.

Main Methods:

Limited proteolysis combined with mass spectrometry (LiP-MS) was employed.
Intact mass spectrometry and top-down analysis identified KRas G12D cleavage products.
Molecular dynamics (MD) simulations analyzed ligand-free and ligand-bound protein structures.

Main Results:

Protease cleavage sites protected by inhibitor binding were identified.
Protection correlated with the switch II binding site of KRas G12D.
Compound binding affinity and functional groups influenced cleavage patterns.

Conclusions:

LiP-MS-MD effectively characterizes small-molecule inhibitor binding to KRas G12D.
This integrated approach can accelerate hit selection in early-stage drug discovery.
LiP-MS-MD offers a valuable orthogonal method for hit validation.