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Sánchez-Serrano discusses the story of the innovative anticancer drug bortezomib to dissect the key public-sector-private sector interactions that made the development of this drug successful despite many barriers, and considers the implications for improving translational research in general. The high price of many innovative drugs, which is in part due to the considerable expense and risk involved in drug development, underlines the need for more efficient approaches to bring drugs to the market, with more effective translational research in particular identified as an important part of such strategies. Here, the development of the cancer drug bortezomib (Velcade; Millennium Pharmaceuticals) by a biotechnology company — Myogenics/ProScript — started by academics from Harvard University is discussed to dissect the key academia–industry/public sector–private sector interactions that made the development of this drug a success despite many barriers. A model to explain how and why bortezomib was approved in record time is presented, and areas for public-policy initiatives to improve translational research in general are highlighted.

In a recent study, using hydrogen cyanide as paradigm, we have shown that pharmacological knowledge evolves non-linearly ( https://pubmed.ncbi.nlm.nih.gov/38900251/ ). The aim of this study was to investigate the changes in the presentation of the drugs pilocarpine and physostigmine in textbooks from 1878 to 2023. The categories of structure, molecular mechanism of action, pharmacokinetics, effects, indications, adverse drug reactions, interactions, and contraindications were evaluated. The pharmacological knowledge on the molecular mechanism, chemical structure, and pharmacokinetics of pilocarpine and physostigmine changed the most during the period of 150 years. Until 1944, textbooks did not mention a molecular mechanism of action of pilocarpine and from 1951 onwards they described the activation of muscarinic acetylcholine receptors as the molecular basis of pilocarpine’s effect. Until 1944, most textbooks on physostigmine also did not mention the molecular mechanism of action. From 1951 onwards, the reversible inhibition of acetylcholinesterase is mentioned as the mechanism of action of physostigmine. In contrast, in the categories effects , indications , adverse drug reactions , interactions , and contraindications , the detected changes in the pharmacological knowledge presented were comparatively smaller. Older pharmacology textbooks were better than newer ones at discussing changes in knowledge and scientific errors. We noted substantial differences in the presentation of pilocarpine and physostigmine among German and US pharmacology textbooks. We show a decline of the clinical relevance of both drugs and their presentation in pharmacological textbooks with physostigmine being virtually irrelevant. But modern textbooks still discuss physostigmine substantially, fitting to studies on the obsolete drug reserpine ( https://pubmed.ncbi.nlm.nih.gov/38103060/ ). Thus, textbooks often far lag clinical practice. Google Scholar conveys the incorrect impression that physostigmine is clinically more relevant than it is. An exponential decline in prescription numbers is a robust indicator of clinical obsolescence. From our study, we extract nine easily implementable take-home messages for future (pharmacology) textbook authors to ensure that this traditional teaching format will prevail against the competition of allegedly more “modern” teaching media.

With the advancement of systems biology research, we have already seen great progress in pharmacology studies, especially in network pharmacology. Network pharmacology has been proven to be effective for establishing the “compounds-proteins/genes-diseases” network, and revealing the regulation principles of small molecules in a high-throughput manner, thus would be very effective for the analysis of drug combinations, especially for TCM preparations. In this work, we have proposed the TCM-Mesh system, which records TCM-related information collected from various resources and could serve for network pharmacology analysis for TCM preparations in a high-throughput manner (http://mesh.tcm.microbioinformatics.org/). Currently, the database contains 6,235 herbs, 383,840 compounds, 14,298 genes, 6,204 diseases, 144,723 gene-disease associations, 3,440,231 pairs of gene interactions, 163,221 side effect records and 71 toxic records, and web-based software construct a network between herbs and treated diseases, which will help to understand the underlying mechanisms for TCM preparations at molecular levels. We have used 1,293 FDA-approved drugs, as well as compounds from an herbal material Panax ginseng and a patented drug Liuwei Dihuang Wan (LDW) for evaluating our database. By comparison of different databases, as well as checking against literature, we have demonstrated the completeness, effectiveness, and accuracy of our database.

The dominant paradigm in drug discovery is the concept of designing maximally selective ligands to act on individual drug targets. However, many effective drugs act via modulation of multiple proteins rather than single targets. Advances in systems biology are revealing a phenotypic robustness and a network structure that strongly suggests that exquisitely selective compounds, compared with multitarget drugs, may exhibit lower than desired clinical efficacy. This new appreciation of the role of polypharmacology has significant implications for tackling the two major sources of attrition in drug development—efficacy and toxicity. Integrating network biology and polypharmacology holds the promise of expanding the current opportunity space for druggable targets. However, the rational design of polypharmacology faces considerable challenges in the need for new methods to validate target combinations and optimize multiple structure-activity relationships while maintaining drug-like properties. Advances in these areas are creating the foundation of the next paradigm in drug discovery: network pharmacology.

This article aims to understand the global and longitudinal trends of research on Panax ginseng. We used bibliometrics to analyze 3974 papers collected from the Web of ScienceTM Core Collection database during 1959–2016. The number of publications showed a steady growth before 2000 and exponentially increased in stage III (2000–2016, about 86% of the papers were published). Research on P. ginseng was conducted in 64 countries, mainly in Asia; in particular, 41% and 28% of the publications were from South Korea and China, respectively. The institutions from South Korea and China had high publication output and close cooperation and provided the majority of financial support. All top 10 authors and four of the top 20 journals in terms of number of publications originated from South Korea. The leading research subjects were pharmacology (39%), plant science (26%), and integrative complementary medicine (19%). The hotspot of P. ginseng research transformed from basic science to application, and multidisciplinary sciences will play a substantial role in the future. This study provides a comprehensive analysis to elucidate the global distribution, collaboration patterns, and research trends in the P. ginseng domain.

This article reviews the origin and evolution of high throughput screening (HTS) through the experience of an individual pharmaceutical company, revealing some of the mysteries of the early stages of drug discovery to the wider pharmacology audience. HTS in this company (Pfizer, Groton, USA) had its origin in natural products screening in 1986, by substituting fermentation broths with dimethyl sulphoxide solutions of synthetic compounds, using 96‐well plates and reduced assay volumes of 50‐100μl. A nominal 30mM source compound concentration provided high μM assay concentrations. Starting at 800 compounds each week, the process reached a steady state of 7200 compounds per week by 1989. Screening in the Applied Biotechnology and Screening Group was centralized with screens operating in lock‐step to maximize efficiency. Initial screens were full files run in triplicate. Autoradiography and image analysis were introduced for 125I receptor ligand screens. Reverse transcriptase (RT) coupled with quantitative PCR and multiplexing addressed several targets in a single assay. By 1992 HTS produced ‘hits’ as starting matter for approximately 40% of the Discovery portfolio. In 1995, the HTS methodology was expanded to include ADMET targets. ADME targets required each compound to be physically detected leading to the development of automated high throughput LC‐MS. In 1996, 90 compounds/week were screened in microsomal, protein binding and serum stability assays. Subsequently, the mutagenic Ames assay was adapted to a 96‐well plate liquid assay and novel algorithms permitted automated image analysis of the micronucleus assay. By 1999 ADME HTS was fully integrated into the discovery cycle. British Journal of Pharmacology (2007) 152, 53–61; doi:10.1038/sj.bjp.0707373

Computational (in silico) methods have been developed and widely applied to pharmacology hypothesis development and testing. These in silico methods include databases, quantitative structure‐activity relationships, similarity searching, pharmacophores, homology models and other molecular modeling, machine learning, data mining, network analysis tools and data analysis tools that use a computer. Such methods have seen frequent use in the discovery and optimization of novel molecules with affinity to a target, the clarification of absorption, distribution, metabolism, excretion and toxicity properties as well as physicochemical characterization. The first part of this review discussed the methods that have been used for virtual ligand and target‐based screening and profiling to predict biological activity. The aim of this second part of the review is to illustrate some of the varied applications of in silico methods for pharmacology in terms of the targets addressed. We will also discuss some of the advantages and disadvantages of in silico methods with respect to in vitro and in vivo methods for pharmacology research. Our conclusion is that the in silico pharmacology paradigm is ongoing and presents a rich array of opportunities that will assist in expediating the discovery of new targets, and ultimately lead to compounds with predicted biological activity for these novel targets. British Journal of Pharmacology (2007) 152, 21–37; doi:10.1038/sj.bjp.0707306

Cancer is a medical problem that has been difficult to overcome on a global scale. Owing to the sharing of single or multiple genes or regulatory modules, cancer treatment often faces severe challenges. The core of network pharmacology lies in constructing human disease gene regulation networks and multi-pharmacology network. With the continuous updating and iteration of new technologies, it is helpful for us to systematically understand the occurrence and development mechanism behind complex diseases and elucidate the pharmacological mechanisms from the perspective of biological network balance. This review aims to clarify the application of network pharmacology in exploring the pharmacological treatment mechanism of natural products, drug repositioning, and new technology combinations in the context of complex pathogenesis of cancer, so as to help realize the full potential of network pharmacology. Additionally, we discuss the future development of network pharmacology to guide clinical diagnosis and treatment. Graphical abstract

Key Points Post-translational modifications of histones, the major protein components of chromatin, provide the mechanistic underpinning for epigenetic regulation of gene transcription. Among the enzymes that modify histones, the protein methyltransferases (PMTs) are particularly attractive as drug targets. A number of PMTs have been directly associated with the pathogenesis of diseases such as human cancers, inflammatory diseases, metabolic diseases, neurodegenerative diseases and other unmet medical needs of patients. The PMT target class is composed of two enzyme families: the protein lysine methyltransferases (PKMTs) and the protein arginine methyltransferases (PRMTs). All of the PMTs use a common, small-molecule cofactor, S -adenosyl- L -methionine (SAM), as the universal methyl donor for the enzymatic methylation of protein lysine and arginine side chains. The universal use of SAM by PMTs is reminiscent of the universal use of ATP by protein kinases, a well-established drug target class of enzymes. As for the ATP-binding pockets of kinases, the SAM-binding pockets of PMTs show substantial structural diversity in terms of both the amino acids that line the enzyme pockets and the conformation of ligands bound in the pockets of various PMTs, as revealed by X-ray crystallographic studies. These results suggest that the development of selective inhibitors of specific PMTs is achievable. Here, we review the biological, biochemical, medicinal chemical and structural biological data that together present the PMTs as a large, pathology-relevant, druggable target class for drug discovery. As for the ATP-binding pocket of kinases, we suggest that the SAM-binding pockets of PMTs provide a clear target for pharmacological modulation of selective PMT activity. The protein methyltransferases (PMTs) are emerging as a group of enzymes that play key parts in human diseases. This Review highlights data that support the validation of PMTs as therapeutic targets, including the structural and mechanistic data that support the concept of the PMTs as a druggable target class. The protein methyltransferases (PMTs) — which methylate protein lysine and arginine residues and have crucial roles in gene transcription — are emerging as an important group of enzymes that play key parts in normal physiology and human diseases. The collection of human PMTs is a large and diverse group of enzymes that have a common mechanism of catalysis. Here, we review the biological, biochemical and structural data that together present PMTs as a novel, chemically tractable target class for drug discovery.

Various drug delivery approaches can be used to maximize therapeutic efficacy and minimize side effects, by impacting absorption, distribution, metabolism, and elimination (ADME) of a drug compound. For those drugs with poor water solubility or low permeability, techniques such as amorphous solid dispersion, liposomes, and complexations have been used to improve their oral bioavailability. Modified release (MR) formulations have been widely used to improve patient compliance, as well as to reduce side effects, especially for those drugs with short half-lives or narrow therapeutic windows. More than ten drugs using sterile long-acting release (LAR) formulations with clear clinical benefit have been successfully marketed. Furthermore, drug delivery systems have been used in delaying drug clearance processes. Additionally, modifying the in vivo drug distribution using targeted delivery systems has significantly improved oncology treatments. All the drug delivery approaches have their advantages and limitations. For both brand and generic drugs, the achievement of consistent quality and therapeutic performance using drug delivery systems can also pose serious challenges in developing a drug for the market, which requires close collaboration among industry, academia, and regulatory agencies. With the advent of personalized medicines, there will be great opportunities and challenges in utilizing drug delivery systems to provide better products and services for patients.