Potential Applications In Drug Discovery Research Articles

Mass spectrometry in medicinal chemistry

Preface. A Personal Foreword. List of Contributors. I Introduction to MS in bioanalysis. 1 Mass Spectrometry in Bioanalysis - Methods, Principles and Instrumentation (Gerard Hopfgartner). 1.1 Introduction. 1.2 Fundamentals. 1.3 Ionization Techniques. 1.4 Mass Analyzers. 1.5 Ion Detectors. 1.6 Practical Aspects and Applications in Bioanalysis. 1.7 Perspectives. 1.8 Common Definitions and Abbreviations. References. II Studying target-ligand interactions analyzing the ligand by MS. 2 Drug Screening Using Gel Permeation Chromatography Spin Columns Coupled with ESI-MS (Marshall M. Siegel). 2.1 Introduction. 2.2 Experimental. 2.3 Results. 2.4 Conclusions. References. 3 ALIS: An Affinity Selection-Mass Spectrometry System for the Discovery and Characterization of Protein-Ligand Interactions (Allen Annis, Cheng-Chi Chuang, and Naim Nazef). 3.1 Introduction. 3.2 ALIS: An Affinity Selection-Mass Spectrometry System based on Continuous SEC. 3.3 Discovery of Ligands from Combinatorial Libraries. 3.4 Quantitative Binding Affinity Measurement. 3.5 Competition-based Binding Site Determination and Affinity Ranking in Mixtures. 3.6 Protein-Ligand Dissociation Rate Measurement. 3.7 Conclusions. 3.8 Future Directions. References. 4 Library Screening Using Ultrafiltration and Mass Spectrometry (Timothy E. Cloutier and Kenneth M. Comess). 4.1 Introduction. 4.2 Ultra-high Throughput Filtration-based Affinity Screening as a Discovery Tool. 4.3 Additional Affinity Screening Methodology That Includes Mass Spectrometry-based Readout. 4.4 Conclusions and Future Directions. References. 5 Continuous-flow Systems for Ligand Binding and Enzyme Inhibition Assays Based on Mass Spectrometry (Hubertus Irth). 5.1 Introduction. 5.2 Continuous-flow Enzyme Assays Based on Mass Spectrometry. 5.3 Continuous-flow Ligand Binding Assays Based on Mass Spectrometry. 5.4 MS Assay Based on Dissociation of Isolated Protein-Ligand Complexes. 5.5 Future Prospects. References. 6 Frontal Affinity Chromatography - Mass Spectrometry for Ligand Discovery and Characterization (Nora Chan, Darren Lewis, Michele Kelly, Ella S.M. Ng, and David C. Schriemer). 6.1 Introduction. 6.2 Enabling FAC with MS Detection. 6.3 System Advancements - Fluidics, Immobilization, Detection. 6.4 Select Applications. 6.5 Summary and Evaluation. References. 7 MS Binding Assays - An Alternative to Radioligand Binding (Georg Ho..fner, Christine Zepperitz, and Klaus T. Wanner). 7.1 Introduction. 7.2 Radioligand Binding Assays. 7.3 MS Binding Assays. 7.4 Summary and Perspectives. References. 8 Laser Desorption Assays - MALDI-MS, DIOS-MS, and SAMDI-MS (Martin Vogel, Andy Scheffer, Andre' Liesener, and Uwe Karst). 8.1 MALDI-MS Assays. 8.2 DIOS: Desorption/Ionization on Silicon. 8.3 SAMDI: Self-assembled Monolayers for MALDI-MS. 8.4 Conclusion. References. III Studying target-ligand interactions analyzing intact target-ligand complexes by MS. 9 Tethering: Fragment-based Drug Discovery by Mass Spectrometry (Mark T. Cancilla and Daniel A. Erlanson). 9.1 Introduction. 9.2 Reduction to Practice. 9.3 Finding Fragments: Thymidylate Synthase Proof of Principle. 9.4 Finding and Linking Fragments in One Step: Tethering with Extenders. 9.5 Conclusions. References. 10 Interrogation of Noncovalent Complexes by ESI-MS: A Powerful Platform for High Throughput Drug Discovery (Steven A. Hofstadler and Kristin A. Sannes-Lowery). 10.1 Analysis of Noncovalent Complexes by ESI-MS. 10.2 Multitarget Affinity/Specificity Screening. 10.3 Multitarget Affinity/Specificity Screening in a High Throughput Format. 10.4 Affinity/Specificity. 10.5 SAR by MS. 10.6 Future Directions. References. IV Studying target-ligand interactions analyzing the target binding site by MS. 11 Quantification of Protein-Ligand Interactions in Solution by Hydrogen/Deuterium Exchange (PLIMSTEX) (Mei M. Zhu, David Hambly, and Michael L. Gross). 11.1 Introduction. 11.2 The PLIMSTEX Method. 11.3 Applications of PLIMSTEX. 11.4 Features of PLIMSTEX. 11.5 Fast Radical Footprinting for Protein-Ligand Interaction Analysis. 11.6 Potential Applications in Drug Discovery. References. 12 Protein-targeting Drug Discovery Guided by Hydrogen/Deuterium Exchange Mass Spectrometry (DXMS) (Yoshitomo Hamuro, Stephen J. Coales, and Virgil L. Woods Jr). 12.1 Introduction. 12.2 Theory of H/D Exchange. 12.3 Overview of H/D Exchange Technologies. 12.4 DXMS-guided Design of Well Crystallizing Proteins. 12.5 Rapid Characterization of Protein Conformational Change with DXMS. 12.6 Application of H/D Exchange to Protein-Small Molecule Ligand Interactions. 12.7 DXMS-guided Design of Small Molecules that Target Protein-Protein Interaction Surfaces. 12.8 Optimal Formulation and Quality Control of Whole-protein Therapeutics with DXMS. 12.9 Conclusions. References. V MS in early pharmacokinetics. 13 Mass Spectrometry in Early Pharmacokinetic Investigations (Walter A. Korfmacher). 13.1 Introduction. 13.2 HPLC-MS/MS Overview. 13.3 In Vitro Applications. 13.4 In Vivo Applications. 13.5 Rapid Method Development. 13.6 Increasing Throughput in HPLC-MS/MS. 13.7 Matrix Effects. 13.8 Discovery PK Assay Rules. 13.9 New Technology in LC-MS. 13.10 Conclusion. References. Index.

In Silico Metabolism Studies in Drug Discovery: Prediction of Metabolic Stability

The strategy to screen compounds solely for pharmacological potency and selectivity in the early stages of drug discovery brought the pharmaceutical industry to face the stark reality of disproportionate attrition later in the development stage due to poor drug disposition characteristics. This attrition contributed to the exorbitant costs of discovering and developing drugs. Considering ADME (Absorption, Distribution, Metabolism, and Excretion) characteristics of compounds early in the discovery process can wisely direct resources to compounds that have greater potential to survive the clinical trial stages of drug development. However, experimental determination of ADME characteristics is not practical for large numbers of compounds. Therefore, focus is being centered on bringing in silico approaches earlier in the discovery process to assess ADME properties solely from molecular structure. Given that metabolism is one of the most important of the ADME properties, in this paper we review a number of metabolism in silico tools and models that have potential applications in drug discovery. We then describe a step-by-step process, as practiced in our laboratories, to construct and deploy reliable in silico metabolic stability and other ADME screens. Additionally, we give examples of the application of our metabolic stability in silico screens in scaffold selection, ADME space enrichment, and rationalizing synthesis and testing of compounds in the drug discovery process. Agreements between the experimental and in silico metabolic stability values ranging from 84% to 100% have convinced many discovery project teams to routinely use these in silico models. Finally, we present our ideas on the successful implementation of in silico models and tools for significant impact on drug discovery and development Keywords: In silico, ADME, metabolism, metabolic stability, drug discovery, QSAR models, ADME software

Impedance labelless detection-based polypyrrole protein biosensor

A simple and sensitive electrochemical immunosensor with impedance labelless detection and novel data processing method was investigated. One-step copolymerization was used to electrochemically deposit an antibody impregnated polypyrrole film on a glassy carbon electrode surface for the immunosensor. Impedance measurements provided a labelless or reporterless method to detect antibody (Ab)-antigen (Ag) interactions. Dimensionless analysis was employed to successfully process the measured impedance data. Since the method derived unit impedance change to eliminate or reduce the variation of the bulk electronic properties of Ab/polypyrrole films, the signal to noise ratio (S/N) was significantly improved for high sensitivity and specificity. Nonspecific binding effect was studied by array electrode chips and was found out that the polypyrrole electrode without antibody attachment had much stronger nonspecific binding effect than the Ab/polypyrrole electrode; incubation followed by thoroughly washing significantly reduced the nonspecific interference. 10 pg/ml detection limit and superior specificity were achieved by the method, demonstrating a highly sensitive labelless immunosensor in comparison with the detection limit of ng -microgram/ml for the reported polypyrrole based immunosensors. The electrochemical immunosensors presented in this paper, due to its simplicity, low cost, high sensitivity and superior specificity, could be an invaluable tool for clinical diagnostics and could have potential applications in drug discovery, environmental and food analysis.

An efficient approach to asymmetric synthesis of dipeptide β-turn mimetics: indolizidinone amino acids

Azabicyclo[ XY0] alkane amino acids are rigid dipeptide β-turn mimetics with great potential applications for drug discovery. The lack of efficient methods to synthesize these compounds is a major bottleneck in this field. Herein we report an efficient approach to the enantiopure synthesis of (3 S,6 S,9 S) and (3 R,6 R,9 R) methyl 2-oxo-3-[ N-(Boc/Cbz)amino]-1-azabicyclo[4.3.0]nonane-9-carboxylates 1 . In this approach, the key intermediates 5a and 5b with different stereochemical configurations were efficiently constructed from the same precursor in high stereoselectivity via asymmetric hydrogenations using ( S, S) or ( R, R) Et-DUPHOS, Rh(I)-based catalysts. The process, starting from inexpensive diethyl 1,3-acetonedicarboxylate 2 , can allow for the practical synthesis of this class of compounds.