Drug Discovery Today. Technologies

In this paper, we review the growing development and applications of supercritical fluid chromatography-mass spectrometry (SFC-MS) for the analysis of small molecular analytes and biomarkers in drug discovery. As an alternative chromatographic technique, SFC instrumentation and methodology have dramatically advanced over the last decade. Mass spectrometry (MS) provides the powerful detection capability as it couples with SFC. A growing number of SFC-MS/MS applications were reported over the last decade and the application areas of SFC-MS/MS is rapidly expanding...

Mass spectrometry plays an essential role in qualitative and quantitative analysis of pharmaceutically relevant molecules. The present review summarizes some the most common applications of LC-MS for the characterization of therapeutic low-molecular-weight compounds, peptides and proteins, and oligonucleotides using low-resolution and high-resolution tandem mass spectrometry. In addition, the benefit of multistage MS, differential ion mobility, and data independent acquisition is emphasized. At last, the potential of coupling MS with novel interfaces for high-throughput analysis is discussed...

As a starting point for drug discovery, affinity selection-mass spectrometry (AS-MS) is ideal for the discovery of lead compounds from chemically diverse sources such as botanical, fungal and microbial extracts. Based on binding interactions between macromolecular receptors and ligands of low molecular mass, AS-MS enables the rapid isolation of pharmacologically active small molecules from complex mixtures for mass spectrometric characterization and identification. Unlike conventional high-throughput screening, AS-MS requires no radiolabels, no UV or fluorescent chromophores, and is compatible with all classes of receptors, enzymes, incubation buffers, cofactors, and ligands...

No abstract text is available yet for this article.

Fragment-based drug discovery (FBDD) emerged as a disruptive technology and became established during the last two decades. Its rationality and low entry costs make it appealing, and the numerous examples of approved drugs discovered through FBDD validate the approach. However, FBDD still faces numerous challenges. Perhaps the most important one is the transformation of the initial fragment hits into viable leads. Fragment-to-lead (F2L) optimization is resource-intensive and is therefore limited in the possibilities that can be actively pursued...

No abstract text is available yet for this article.

One of the remaining bottlenecks in fragment-based drug design (FBDD) is the initial exploration and optimization of the identified hit fragments. There is a growing interest in computational approaches that can guide these efforts by predicting the binding affinity of newly designed analogues. Among others, alchemical free energy (AFE) calculations promise high accuracy at a computational cost that allows their application during lead optimization campaigns. In this review, we discuss how AFE could have a strong impact in fragment evolution, and we raise awareness on the challenges that could be encountered applying this methodology in FBDD studies...

This review provides an overview of the various theoretical and practical aspects of biotech plant design. It covers engineering, quality, regulatory, safety, environmental and economical points to be considered. Current knowledge and future trends as well as their impact on the planning and design are also discussed.

Matrix-assisted laser desorption/ ionization (MALDI) is a soft ionization technique for introducing wide range of analytes into a mass spectrometer (MS). MALDI MS is a powerful tool in drug discovery research and development, providing a high-throughput molecular analysis technique in both preclinical and clinical systems. In particular, MALDI MS is invaluable in the study of peptides and proteins that drive all biological functions. This technology is label-free, provides high specificity in molecular identification, and is high-throughput...

No abstract text is available yet for this article.

No abstract text is available yet for this article.

Bispecific antibodies combine the specificity of two antibodies into one molecule. During the past two decades, advancement in protein engineering enabled the development of more than 100 bispecific formats, three of which are approved by the FDA for clinical use. In parallel to protein engineering methods, advancement in conjugation chemistries have spurred the use of chemical engineering approaches to generate bispecific antibodies. Herein, we review selected chemical strategies employed to generate bispecific antibodies that cannot be made using protein engineering methods...

No abstract text is available yet for this article.

During the last years, X-ray free electron lasers (XFELs) have emerged as X-ray sources of unparalleled brightness, delivering extreme amounts of photons in femtosecond pulses. As such, they have opened up completely new possibilities in drug discovery and structural biology, including studying high resolution biomolecular structures and their functioning in a time resolved manner, and diffractive imaging of single particles without the need for their crystallization. In this perspective, we briefly review the operation of XFELs, their immediate uses for drug discovery and focus on the potentially revolutionary single particle diffractive imaging technique and the challenges which remain to be overcome to fully realize its potential to provide high resolution structures without the need for crystallization, freezing or the need to keep proteins stable at extreme concentrations for long periods of time...

Mass spectrometry imaging (MSI) has become a powerful method for mapping metabolite distribution in a tissue. Applied to bacterial colonies, MSI has a bright future, both for the discovery of new bioactive compounds and for a better understanding of bacterial antibiotic resistance mechanisms. Coupled with separation techniques such as ion mobility mass spectrometry (IM-MS), the identification of metabolites directly on the image is now possible and does not require additional analysis such as HPLC-MS/MS. In this article, we propose to apply a semi-targeted workflow for rapid IM-MSI data analysis focused on the search for bioactive compounds...

The field of proteomics immensely depends on data generation and data analysis which are thoroughly supported by software and databases. There has been a massive advancement in mass spectrometry-based proteomics over the last 10 years which has compelled the scientific community to upgrade or develop algorithms, tools, and repository databases in the field of proteomics. Several standalone software, and comprehensive databases have aided the establishment of integrated omics pipeline and meta-analysis workflow which has contributed to understand the disease pathobiology, biomarker discovery and predicting new therapeutic modalities...

Spatial proteomics has provided important insights into the relationship between protein function and subcellular location. Localization of Organelle Proteins by Isotope Tagging (LOPIT) and its variants are proteome-wide techniques, not matched in scale by microscopy-based or proximity tagging-based techniques, allowing holistic mapping of protein subcellular location and re-localization events downstream of cellular perturbations. LOPIT can be a powerful and versatile tool in drug discovery for unlocking important information on disease pathophysiology, drug mechanism of action, and off-target toxicity screenings...

Data-independent acquisition (DIA) proteomics is a recently-developed global mass spectrometry (MS)-based proteomics strategy. In a DIA method, precursor ions are isolated into pre-defined isolation windows and fragmented; all fragmented ions in each window are then analyzed by a high-resolution mass spectrometer. DIA proteomics analysis is characterized by a broad protein coverage, high reproducibility, and accuracy, and its combination with advances in other techniques such as sample preparation and computational data analysis could lead to further improvements in assay performances...

Drug disposition in children is different compared to adults. Growth and developmental change the processes involved in drug disposition and efficacy, including membrane transporters and drug metabolizing enzymes, but for many of these proteins, the exact changes have not been fully elucidated to date. Quantitative proteomics offers a solution to analyze many DME and DT proteins at once and can be performed with very small tissue samples, overcoming many of the challenges previously limiting research in this pediatric field...

Membrane proteins mediate various biological processes. Most drugs commercially available target proteins on the cell surface. Therefore, proteomics of plasma membrane proteins provides useful information for drug discovery. However, membrane proteins are one of the most difficult biological groups to quantify by proteomics because of their hydrophobicity and low protein content. To obtain unbiased quantitative membrane proteomics data, specific strategies should be followed during sample preparation. This review explores the most recent advances in sample preparation for the quantitative analysis of the membrane proteome, including enrichment by subcellular fractionation and trypsin digestion...