The drug discovery process typically involves disease target identification and/or validation, generation of highly potent molecules that target specific proteins, characterization of pharmacokinetics, drug metabolism, pharmacodynamics, and toxicology for drug candidates, followed by intensive clinical studies and pharmaceutical development activities to bring the drug to market. Analytical techniques are fundamentally important to enabling all phases of this process and with advances in qualitative and quantitative measurements can lead to both process and product innovations. The scientific principles behind analytical techniques are complex and a myriad of analytical instruments and applications are needed at every step of the drug discovery and development process for both small molecule pharmaceuticals and protein therapeutics.
The first of the three downloads is an article by Alfonso Espada and Manuel Molina-Martin from Eli Lilly in Spain titled ‘Capillary electrophoresis and small molecule drug discovery: a perfect match?’ Capillary electrophoresis (CE) is an analytical technique based on the separation of analytes within a capillary owing to their different electrophoretic mobilities. It has matured to become an integral part of pharmaceutical research due to its tremendous versatility, simplicity of use, analytical data quality and cost-effectiveness. The authors suggest that the flexibility of CE and related techniques provides an extremely powerful tool for scientists to obtain qualitative and quantitative information at all the stages of small molecule drug discovery. Recent technological advances in the field have enabled CE to become affordable in areas of drug discovery where high-performance liquid chromatography (HPLC) is already well established, such as for HTS, proteomics, metabolomics and biomarker discovery.
The second article titled ‘How to conduct and interpret ITC experiments accurately for cyclodextrin–guest interactions’ is written by Kawthar Bouchemal and Silvia Mazzaferro from Universite´ Paris-Sud in France. The isothermal titration calorimetry (ITC) technique is based on measurement of the heat generated or absorbed upon the interaction between two molecules. It is the most sensitive method available for determining the stoichiometry of interactions, the affinity constant and the enthalpy change reflecting the heat released or taken up during an interaction. In this review, authors explain how to conduct ITC experiments correctly for cyclodextrin (CD)–drugs interactions in choosing an accurate fitting model for the titration curve and interpreting the ITC results. ITC experiments can provide characterization of CD–drug interactions with quantitative measurements in a label-free manner. The authors also describe the use of ITC for the characterization of CD-containing nanoparticles.
The final article ‘Characterization of protein therapeutics by mass spectrometry: recent developments and future directions’ written by Bethanne M. Warrack, Angela K. Goodenough, Hui Wei, David B. Wang-Iverson, Adrienne A. Tymiak and me describes recent developments and future trends in the characterization of protein therapeutics using mass spectrometry (MS). As one of the most highly utilized analytical techniques in drug discovery, MS is used widely for the characterization of protein therapeutics because of its analytical sensitivity, selectivity and specificity. As suggested by the authors, top-down MS for protein and/or peptide sequencing will continue to evolve into mature methodologies for characterization of post-translational modifications, including identifying the sites of modifications and the nature and abundance of modified species. Further MS instrumentation development and software integration are keys to making top-down MS more accessible to scientists as a valuable tool in protein characterization. Hydrogen/Deuterium exchange MS and ion mobility MS can provide information on higher order structures of protein therapeutics. Quantitative measurements based on MS are now emerging as an orthogonal approach to traditional ligand-binding assays for in vivo analysis of protein therapeutics in biological matrices.
Overall, the three articles illustrate the versatility and utility of analytical techniques as enabling tools in drug discovery. The complexity in using these analytical techniques is also clearly evident in the cited articles. In the future, continued advances in analytical instrumentation and scientific expertise of scientists will be needed to ensure success in providing analytical solutions to key problems and transforming innovations in pharmaceutical research.
Dr Guodong Chen has extensive pharmaceutical research experience in major pharmaceutical companies, including Eli Lilly and Co., Schering-Plough (now Merck) and Bristol-Myers Squibb. He currently heads an analytical/mass spectrometry group at Bristol-Myers Squibb’s Princeton site, providing analytical support to drug discovery programs and development projects in small molecule pharmaceuticals and biologics. He is the author and/or co-author of over 60 research publications in peer-reviewed journals/book chapters, and co-editor of two books on mass spectrometry in drug discovery. He is a frequently invited speaker at conferences and academic institutes with over 75 presentations. He also organized/chaired scientific sessions at various forums, including major sessions on small molecule pharmaceuticals and biologics at EAS, Pittcon, ASMS conference and ACS meetings. Dr Chen received his Ph.D. in Analytical Chemistry from Purdue University under the direction of Professor R. Graham Cooks.