Drug Discovery Today: Technologies最新文献

As graph neural networks are becoming more and more powerful and useful in the field of drug discovery, many pharmaceutical companies are getting interested in utilizing these methods for their own in-house frameworks. This is especially compelling for tasks such as the prediction of molecular properties which is often one of the most crucial tasks in computer-aided drug discovery workflows. The immense hype surrounding these kinds of algorithms has led to the development of many different types of promising architectures and in this review we try to structure this highly dynamic field of AI-research by collecting and classifying 80 GNNs that have been used to predict more than 20 molecular properties using 48 different datasets.

Small molecule induced protein degradation has created tremendous excitement in drug discovery within recent years. Not being confined to target inhibition and being able to remove disease-causing protein targets via engagement and subsequent ubiquitination has provided scientists with a powerful tool to expand the druggable space. At the center of this approach sits the ternary complex formed between an E3 ubiquitin ligase, the small molecule degrader, and the target protein. A productive ternary complex is pivotal for a ubiquitin to be transferred to a surface lysine of the target protein resulting in poly-ubiquitination which enables recognition and finally degradation by the proteasome. As understanding the ternary complex means understanding the degradation process, many efforts are put into obtaining structural information of the ternary complex and getting a snapshot of the underlying conformations and molecular contacts. Locking this transient trimeric intermediate in a crystalline state has proven to be very demanding but the obtained results have tremendously improved our understanding of small molecule degraders. This review discusses target protein degradation from a structural perspective and highlights the evolution of certain degraders based on the obtained structural insights.

Since the early 2010s, cryo-electron microscopy (cryo-EM) has evolved to a mainstream structural biology method in what has been dubbed the “resolution revolution”. Pharma companies also began to use cryo-EM in drug discovery, evidenced by a growing number of industry publications. Hitherto limited in resolution, throughput and attainable molecular weight, cryo-EM is rapidly overcoming its main limitations for more widespread use through a new wave of technological advances. This review discusses how cryo-EM has already impacted drug discovery, and how the state-of-the-art is poised to further revolutionize its application to previously intractable proteins as well as new use cases.

High concentration monoclonal antibody drug products represent a special segment of biopharmaceuticals. In contrast to other monoclonal antibody products, high concentration monoclonal antibodies are injected subcutaneously helping increase patient compliance and reduce the number of hospital patient visits. It is important to note that a high protein concentration (≥50 mg/mL) poses a challenge from a product development perspective. Colloidal properties, physical and chemical protein stability should be considered during formulation, primary packaging and manufacturing process development as well as optimization of other dosage form-related parameters. The aim of such development work is to obtain a drug product capable of maintaining appropriate protein structure throughout its shelf-life and ensure proper and accurate dosage upon administration.

Recombinant proteins used in biomedical research, diagnostics and different therapies are mostly produced in Chinese hamster ovary cells in the pharmaceutical industry. These biotherapeutics, monoclonal antibodies in particular, have shown remarkable market growth in the past few decades. The increasing demand for high amounts of biologics requires continuous optimization and improvement of production technologies. Research aims at discovering better means and methods for reaching higher volumetric capacity, while maintaining stable product quality. An increasing number of complex novel protein therapeutics, such as viral antigens, vaccines, bi- and tri-specific monoclonal antibodies, are currently entering industrial production pipelines. These biomolecules are, in many cases, difficult to express and require tailored product-specific solutions to improve their transient or stable production. All these requirements boost the development of more efficient expression optimization systems and high-throughput screening platforms to facilitate the design of product-specific cell line engineering and production strategies. In this minireview, we provide an overview on recent advances in CHO cell line development, targeted genome manipulation techniques, selection systems and screening methods currently used in recombinant protein production.

The emergence of fungal infection is a growing public health concern that in the latest years is becoming a serious threat to humans, particularly for immunocompromised individuals. Invasive fungal infections (IFIs), which are associated with significant morbidity and mortality, are on the rise due to the availability of only a few old antifungal agents. In addition to this, the growing use of antibiotics makes the population increasingly susceptible to these infections. Since carbohydrates are the main component of the fungal cell wall, the study of fungal glycans as potential targets for the fight against IFIs has aroused much interest in recent decades. In most fungal species the saccharides of the core are made up of chitin and β-glucans, while the outer layer carbohydrates vary according to the fungal species, such as mannans for Candida albicans, galactomannans for Aspergillus fumigatus hyphae, α-glucans for Aspergillus fumigatus and Cryptococcus neoformans, glucuronoxylomannans (GXM) and galactoxylomannans (GalXM) for Criptococcus neoformans. Being surface antigens, fungal carbohydrates are a logical target for the development of antifungal glycoconjugate vaccines and for immunotherapy with monoclonal antibodies. This review summarizes recent findings on active and passive immunization strategies based on fungal carbohydrates explored preclinically for three of the major fungal pathogens: Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus.

The pharmaceutical industry is highly reliant on researchers who not only possess the technical knowledge but also the professional skills to collaborate in drug development. To prepare future practitioners to thrive in this interdisciplinary environment, Innovative Training Networks (ITNs) have become increasingly important in doctoral training. In this piece, we explore the benefits of these ITNs in training future practitioners in drug discovery. Through a bibliometric review, we find that the top researchers in fragment-based drug discovery have a high degree of collaboration and mobility across institutes. We then investigate which aspects of the ITN training program enable PhD students to gain these skills. We find that secondments, the short-term stays that students have in partner research institutes, are useful in preparing students to have both broad knowledge of drug discovery and specialization in their field of interest. Aside from imparting technical skills, we find that the collaborative environment in ITNs enables students to communicate better and to work effectively in teams. Doctoral students benefit by being exposed to relevant experiences that they can later apply as they navigate through the complex web of relationships and competencies in the industry. We conclude by recommending best practices to further improve ITNs in the training of future practitioners.

In this review, we present an overview of some of the medicinally-relevant organometallic drugs that have been used in the past or that are currently in clinical trials as well as an example of compounds that are currently in the initial stage of drug development. Three main classes of organometallic complexes have been chosen for discussion: antimicrobial organoarsenicals, antimalarial and anticancer ferrocene-containing compounds and anticancer catalytic organometallic complexes. The purpose of this review is to provide readers with a focus on the significant progress that has been made for each of these respective fields of medicine.

The key factor in successful development and marketing of biosimilar antibodies is a deep understanding of their critical quality attributes and the ability to control them. Comprehensive functional characterization is therefore at the heart of the process and is a crucial part of regulatory requirements. Establishment of a scientifically sound molecule-specific functional in vitro assay panel requires diligent planning and high flexibility in order to respond to both regulatory requirements and the ever-changing demands relevant to the different stages of the development and production process. Relevance of the chosen assays to the in vivo mechanism of action is of key importance to the stepwise evidence-based demonstration of biosimilarity. Use of a sound interdisciplinary approach and orthogonal state-of-the-art techniques is also unavoidable for gaining in-depth understanding of the biosimilar candidate.

The aim of the present review is to give a snapshot on the methodic landscape as depicted by the available literature discussing the in vitro techniques used for the functional characterization of approved biosimilar therapeutic antibodies. Emerging hot topics of the field and relevant structure-function relationships are also highlighted.