Drug Discovery Today: Technologies最新文献

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. Here, we discuss technical concepts of LOPIT with its potential applications in drug discovery and development research.

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.

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. The first part of this review is devoted to the different aspects of SFC-MS development and recent technological advancements. In the second part of this review, we highlight the recent application areas in pharmaceutical research and development.

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. Liquid chromatography tandem mass spectrometry (LC–MS/MS) based methods for quantification of (membrane) proteins has evolved as a golden standard for proteomic analysis. The last years, big steps have been made in maturation studies of hepatic and renal drug transporters and drug metabolizing enzymes using this method. Protein and organ specific maturation patterns have been identified for the human liver and kidney, which aids pharmacological modelling and predicting drug dosing in the pediatric population. Further research should focus on other organs, like intestine and brain, as well as on innovative methods in which proteomics can be used to further overcome the limited access to pediatric tissues, including liquid biopsies and organoids. In this review there is aimed to provide an overview of available human pediatric proteomics data, discuss its challenges and provide guidance for future research.

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. MALDI MS has been used in biomarker discovery and quantitation in virtually all tissues, serum, plasma, CSF, and urine for diagnostics, patient stratification, and monitoring drug efficacy. Other applications include characterization of biological drugs, spatial mapping of biomarkers and drugs in tissues, drug screening, and toxicological assessment.

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. In silico strategies play an important role in F2L, as they can perform a deeper exploration of chemical space, prioritize molecules with high probabilities of being active and generate non-obvious ideas. Here we provide a critical overview of current in silico strategies in F2L optimization and highlight their remarkable impact. While very effective, most solutions are target- or fragment- specific. We propose that fully integrated in silico strategies, capable of automatically and systematically exploring the fast-growing available chemical space can have a significant impact on accelerating the release of fragment originated drugs.

Standing amidst the COVID-19 pandemic, we have faced major medical and economic crisis in recent times which remains to be an unresolved issue till date. Although the scientific community has made significant progress towards diagnosis and understanding the disease; however, effective therapeutics are still lacking. Several omics-based studies, especially proteomics and interactomics, have contributed significantly in terms of identifying biomarker panels that can potentially be used for the disease prognosis. This has also paved the way to identify the targets for drug repurposing as a therapeutic alternative. US Food and Drug Administration (FDA) has set in motion more than 500 drug development programs on an emergency basis, most of them are focusing on repurposed drugs. Remdesivir is one such success of a robust and quick drug repurposing approach. The advancements in omics-based technologies has allowed to explore altered host proteins, which were earlier restricted to only SARS-CoV-2 protein signatures. In this article, we have reviewed major contributions of proteomics and interactomics techniques towards identifying therapeutic targets for COVID-19. Furthermore, in-silico molecular docking approaches to streamline potential drug candidates are also discussed.