Experimental free ligand conformations: a missing link in structure-based drug discovery

• Published in: Future medicinal chemistry Vol. 11; no. 2; pp. 79 - 82
• Main Authors: Chiarparin, Elisabetta, Packer, Martin J, Wilson, David M
• Format: Journal Article
• Language: English
• Published: England Future Science Ltd 01.01.2019; Newlands Press 01.01.2019
• Subjects: Apoptosis; Binding sites; Conformational analysis; Crystallography; Crystallography, X-Ray - methods; Design; Drug Design; Drug development; Drug Discovery - methods; free ligand conformations; Humans; Kinases; Ligands; Magnetic Resonance Spectroscopy - methods; medicinal chemistry; Molecular Conformation; NMR; Nuclear magnetic resonance; Pharmaceutical sciences; Preferences; Protein Binding; protein structure; Proteins; Proteins - chemistry; Proteins - metabolism; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Structure-Activity Relationship; structure-based drug discovery; x-ray; protein structure; free ligand conformations; NMR; structure-based drug discovery; x-ray; medicinal chemistry
• ISSN: 1756-8919; 1756-8927
• DOI: 10.4155/fmc-2018-0339

A range of recent structure-based drug discovery case studies demonstrate the power of nuclear magnetic resonance (NMR) conformational analysis to elucidate SAR trends with respect to conformational preferences of the free ligand (4-14). [...]with the advent of high performance computing, a combination of NMR data and theoretical models can be used to rapidly quantify the populations of all accessible conformers of a ligand in a relatively short timeframe. In AstraZeneca, efforts are ongoing to automate and routinely integrate potency and simple proton NMR data with structural information to enhance the structure-based drug design paradigm, with the ultimate intent of accelerating project cycle times. [...]to derive synergy through the combination of x-ray structure and free ligand NMR conformations, and achieve a turnaround compatible with ‘design, make, test, analyze’ cycle times, it is crucial to establish a collaborative culture among the different disciplines involved in drug optimization.