Proteins are indispensable to all biological systems and drive life processes through activities that are intricately linked to their three-dimensional(3D)structures.Traditional proteomics often provides static snapsh...Proteins are indispensable to all biological systems and drive life processes through activities that are intricately linked to their three-dimensional(3D)structures.Traditional proteomics often provides static snapshots of protein expression,leaving unanswered questions about how proteins respond to stimuli and affect cellular functions.Limited proteolysis coupled with mass spectrometry(LiP-MS)has emerged as a powerful technique for exploring protein structure and function under near-natural conditions.Studies have revealed that LiP-MS is invaluable for structural and functional proteomics because it offers novel insights into protein dynamics.In this review,we summarise the current applications of LiP-MS in diverse areas such as the discovery and identification of drug targets,metabolite action mechanisms,proteome dynamics,protein interactions,and disease biomarkers.We also address the critical challenges in ongoing research and discuss their broader implications for advancing our understanding of protein biology and drug discovery.LiP-MS holds significant promise for accelerating biomarker and therapeutic target development as well as advancing molecular biology research in animals,plants,and microorganisms.展开更多
Polypharmacology,which focuses on designing drugs to target multiple receptors,has emerged as a new paradigm in drug discovery.To rationally design multi-target drugs,it is fundamental to understand protein-ligand int...Polypharmacology,which focuses on designing drugs to target multiple receptors,has emerged as a new paradigm in drug discovery.To rationally design multi-target drugs,it is fundamental to understand protein-ligand interactions on a proteome scale.We have developed a Proteome-wide Off-target Pipeline （POP） that integrates ligand binding site analysis,protein-ligand docking,the statistical analysis of docking scores,and electrostatic potential calculations.The utility of POP is demonstrated by a case study,in which the molecular mechanism of anti-cancer effect of Nelfinavir is hypothesized.By combining structural proteome-wide off-target identification and systems biology,it is possible for us to correlate drug perturbations with clinical outcomes.展开更多
基金supported by the National Natural Science Foundation of China(Grant No.:22304002).
文摘Proteins are indispensable to all biological systems and drive life processes through activities that are intricately linked to their three-dimensional(3D)structures.Traditional proteomics often provides static snapshots of protein expression,leaving unanswered questions about how proteins respond to stimuli and affect cellular functions.Limited proteolysis coupled with mass spectrometry(LiP-MS)has emerged as a powerful technique for exploring protein structure and function under near-natural conditions.Studies have revealed that LiP-MS is invaluable for structural and functional proteomics because it offers novel insights into protein dynamics.In this review,we summarise the current applications of LiP-MS in diverse areas such as the discovery and identification of drug targets,metabolite action mechanisms,proteome dynamics,protein interactions,and disease biomarkers.We also address the critical challenges in ongoing research and discuss their broader implications for advancing our understanding of protein biology and drug discovery.LiP-MS holds significant promise for accelerating biomarker and therapeutic target development as well as advancing molecular biology research in animals,plants,and microorganisms.
基金supported by the National Institutes of Health GM078596High Performance Computing Center at The City University of New York
文摘Polypharmacology,which focuses on designing drugs to target multiple receptors,has emerged as a new paradigm in drug discovery.To rationally design multi-target drugs,it is fundamental to understand protein-ligand interactions on a proteome scale.We have developed a Proteome-wide Off-target Pipeline （POP） that integrates ligand binding site analysis,protein-ligand docking,the statistical analysis of docking scores,and electrostatic potential calculations.The utility of POP is demonstrated by a case study,in which the molecular mechanism of anti-cancer effect of Nelfinavir is hypothesized.By combining structural proteome-wide off-target identification and systems biology,it is possible for us to correlate drug perturbations with clinical outcomes.
