Single cell RNA sequencing technology applicated for drug discovery / 药学学报

Single cell RNA sequencing (scRNA-seq) is an advanced technology to study the transcriptome information at the single cell level. The application of this technology can attribute to analyze the heterogeneous map of cells in the process of disease development, and precisely identify the specific cell subsets that are responsive to pharmacological therapy. Currently, scRNA-seq technology has been widely applied in the field of drug research, including studies on therapeutic targets, drug-induced adverse reactions, drug resistance and vaccine. This work reviews the application of scRNA-seq technology in drug discovery, which offers a scientific basis for personalized and accurate medication therapy.

First-in-class small molecule drugs in 2022 / 药学学报

2022 is the third year of the global COVID-19 pandemic, and its troubles on new drug discovery are gradually apparent. 37 new drugs were approved by the FDA's Center for Drug Evaluation and Research (CDER) last year, down from the peak of 50 new drug approvals in 2021. Notably, first-in-class drugs still occupy a dominant position this year, with a total of 21 drugs. Among them, 7 are first-in-class small molecule drugs. Although the total number of new drug approvals in 2022 sharply decreased, some first-in-class small molecule drugs were regarded as significant, including mitapivat, the first oral activator targeting the pyruvate kinase (PK); mavacamten, the first selective allosteric inhibitor targeting the myocardial β myosin ATPase; deucravacitinib, the first deuterated allosteric inhibitor targeting the tyrosine kinase 2 (TYK2); and lenacapavir, the first long-acting inhibitor targeting the HIV capsid. Generally, the research of first-in-class drugs needs to focus on difficult clinical problems and can treat some specific diseases through novel targets and biological mechanisms. There are tremendous challenges in the research processes of new drugs, including biological mechanism research, target selection, molecular screening, lead compound identification and druggability optimization. Therefore, the success of first-in-class drugs development has prominent guidance significance for new drug discovery. This review briefly describes the discovery background, research and development process and therapeutic application of 3 first-in-class small molecule drugs to provide research ideas and methods for more first-in-class drugs.

Non clinical pharmacodynamic evaluation system of high-altitude hypoxic brain injury / 药学学报

The air at high altitude is thin and belongs to the environment of low temperature, low oxygen and low pressure. The human brain is the most sensitive to hypoxia. Hypoxia will cause dysfunction of the central nervous system, resulting in high-altitude hypoxic brain injury, including mild high altitude headache and more destructive high altitude cerebral edema (HACE). Recently, with more and more people work and live in high altitude areas, the development of high-altitude hypoxic brain injury drugs would produce great economic value and social significance. Non clinical pharmacodynamic evaluation is the basic of drug development, which plays a key role in improving the success rate of clinical transformation and reducing the risk of clinical research. This review summarizes the cell models and animal models, and the evaluation indicators usually used to explore the candidates of high-altitude hypoxic brain injury. We aim at establishing a standardized non clinical efficacy evaluation system for high altitude hypoxic encephalopathy, and provide a standardized reference for drug development in hypoxic encephalopathy at high altitude at nonclinical stage.

Screening methods of SARS-CoV-2 main protease inhibitors and current applications / 药学学报

COVID-19 epidemic continues to spread around the world till these days, and it is urgent to develop more safe and effective new drugs. Due to the limited P3 biosafety laboratories for directly screening inhibitors of virulent viruses with high infectivity, it is necessary to develop rapid and efficient screening methods for viral proteases and other related targets. The main protease (Mpro), which plays a key role in the replication cycle of SARS-CoV-2, is highly conserved and has no homologous proteases in humans, making it an ideal target for drug development. From two different levels, namely, molecular level and cellular level, this paper summarizes the reported screening methods of SARS-CoV-2 Mpro inhibitors through a variety of representative examples, expecting to provide references for further development of SARS-CoV-2 Mpro inhibitors.

Progress of the development of anti-COVID-19 drugs / 药学学报

Since the outbreak of the novel coronavirus (SARS-CoV-2) disease COVID-19 (also known as 2019-nCoV) caused by SARS-CoV-2 in the end of 2019, it has spread rapidly in worldwide. Besides developing effective vaccines, it is urgent to develop safe and effective anti-SARS-CoV-2 drugs to fight this disease. Paxlovid, molnupiravir, sotrovimab and bebtelovimab are urgently authorized by FDA have been proved to be effective against Omicron. This manuscript mainly reviews the recent progress of effective inhibitors against the virus in the world, including receptor inhibitors, antibodies, natural product inhibitors, synthetic inhibitors and broad-spectrum antiviral drugs that are effective against other RNA viruses.

Drug discovery from viewpoint of medicinal chemists / 药学学报

Taking patient needs as the core and realizing clinical value as the guidance are the purpose and path of drug discovery. Whether the first-in-class drug or follow-on drugs are all to meet the demands of patients for drugs that are not treatable or more safe and effective. In order to realize clinical value, innovative drugs driven by basic biological research include three elements: understanding the molecular mechanism of pathogenesis; Grasping the microscopic features of the disease; clarifying the mechanism of action of drugs. The interrelation among the three is the translational medicine, and the medicinal chemistry plays an important role in the translations. That is, based on the results of basic research in biology/medicine, knowledge of the molecular mechanism of disease depends upon the establishment of various in vitro/in vivo models to find the key node and molecular regulation for the treatment of disease. Combined with the knowledge of gene deletion and variation, proteomics, epigenetics and other technologies, the molecular mechanism of disease provides multi-molecular information on the level of gene, proteins, enzymes, receptors, ion channels and signal transduction for molecular drug design. Insight into the microscopic characteristics of diseases would deepen the understanding of the molecular mechanism of the pathogenesis, as well as provide a feasible scientific path for the creation of new drugs. When the molecular mechanism of disease and the action mechanism of drugs are clarified, we have a deeper and wider understanding of the application of existing drugs (or active compounds), and may offer new ideas for drug design and application. In this translational process the medicinal chemistry plays a key role which requires medicinal chemists to break through the habitual thinking and working mode, backtracking (upstream) to basic research and its achievements and applying to the direction of creating new drugs in time, as well as paying attention to the clinical requirements (downstream) and implementing the specific content of the transformation process for the R&D of innovative drugs.

Research progress of natural products for the treatment of hyperuricemia and gout / 药学学报

Although current synthetic anti-gout drugs have significant therapeutic effects in reducing serum uric acid levels, they have serious side effects such as allergic reactions and liver and kidney damage. Natural products with a wide range of uric acid-lowering and high safety have played a critical role in anti-gout drug discovery and development. This paper reviews the natural products with uric acid-lowering or anti-gout pharmacological effects and the investigation on their mechanisms of action, to provide information for drug discovery and development.

Current status of treatment and drug discovery for neuropathic pain / 药学学报

Neuropathic pain (NP) is a medical problem that has been bothering human beings and seriously affects people's quality of life. Although great progress has been made in the study of NP in recent years, there are still many patients who are ineffective to the existing treatments. At present, drug therapy is still the main method to relieve pain, however, adverse drug reactions has hindered the curative effects of drugs. It is extremely urgent to find new drug targets and reduce the adverse effects of existing drugs. This review will mainly describe the current situation and pathogenesis of neuropathic pain, effectiveness and limitations of existing drugs for treating neuropathic pain, and the current status of drug discovery.

First-in-class small molecule drugs in 2020 / 药学学报

With the development of the research on innovative drugs in our country, first-in-class drugs are becoming a main goal for both pharmaceutical companies and scientific institutions. Discovery of first-in-class drugs require amounts of basic research, a massive investment and novel methods, acting as a beacon for the new drug development. In 2020, FDA totally approved 53 novel drugs with 38 small molecules, which still accounting for a major component. Among them, many first-in-class drugs are important including a first EZH2 inhibitor (tazemetostat) for the treatment of epithelioid sarcoma, a first attachment inhibitor (fostemsavir) with novel mechanism for the treatment of HIV, a first farnesyltransferase inhibitor (lonafarnib) for the treatment of Hutchinson-Gilford progeria syndrome (HGPS) and a first MC4 receptor agonist for the treatment of rare genetic diseases of obesity, etc. The research procedures of the above drugs are representative with new ideas. In this review, we outline 3 of the first-in-class drugs to discuss the research background, discovery and development process as well as the therapeutic potentials to provide methods and ideas for the further drug development.

Identification and application of biomarkers in life cycle of drugs / 药学学报

Biomarkers are defined as a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention. Biomarkers can help the decision-making process for new drug research and development, provide guidance for the early clinical development of candidate drugs and reduce the risk of failure. Therefore, as a key factor in the development of new drugs, the discovery and research on biomarkers has increased the interest of the pharmaceutical industry and regulatory agencies. Guidelines on the development and use of biomarkers have been issued by drug regulatory agencies including the EMA, FDA and ICH. Biomarkers are encouraged to be used to facilitate drug development by these relevant regulatory agencies, and also to be used to monitor the safety and efficacy of drugs in post-marketing drug surveillance. The application of biomarkers is encouraged at different stages of a drug's life cycle, including at the stage of basic science research and target identification, prototype design or discovery, preclinical development, clinical development, FDA filling/approval and launch, as well as post-marketing was reviewed. The identification, development, and application of biomarkers in pharmaceutical research is discussed.

Evaluation of non-clinical anxiety disorder models / 药学学报

Anxiety disorders are one of the most common mental disorders in adults, the cause of which derives from a combination of genetics and environmental factors. A series of animal models have been established according to their pathogenesis to measure the level of anxiety or induce anxiety only, and these models have been widely applied in the non-clinical evaluation of anxiolytics. In this review, we present the current trends in the study of anxiety disorders and summarize typical non-clinical anxiety animal models, including models that both measure anxiety levels and induce anxiety, and models that induce anxiety only. This review summarizes the important issues in standardized non-clinical research of anxiety disorders and proposes criteria for the selection of an appropriate R&D model.

Progress in molecularly targeted anti-tumor drugs derived from natural products or their derivatives / 药学学报

Conventional chemotherapy drugs, molecularly targeted drugs, and immune checkpoint inhibitors are the major constituents of anti-tumor drugs in clinical settings at present. Molecularly targeted drugs specifically target the key proteins, genes, or signal transduction pathways in tumor cells which are essential for initiation and development of tumor, resulting in selective activity to induce cell death or growth inhibition. Molecularly targeted drugs have emerged as the mainstream in the research and development of anti-tumor drugs due to its high selectivity and low toxicity. Natural products refer to the chemical constituents or metabolites originated animals, plants, or microorganisms, which have been recognized as one of the important sources of drug discovery with abundant resources and diversified structures. At present, a number of molecularly targeted anti-tumor drugs derived from natural products or their derivatives have been approved for cancer therapy or in clinical trials. This review will summarize the molecularly targeted anti-tumor drugs derived from natural products or their derivatives according to their different cellular targets, and also outline the molecular mechanism, progress, and perspectives of these drugs.

Exploration of nonclinical pharmacodynamics evaluation system of Alzheimer's disease / 药学学报

Alzheimer's disease (AD) is the most common neurodegenerative disease that causes dementia among elderly people. The pathogenesis of AD is still unclear, and currently approved drugs only provide symptomatic benefits and do not prevent or delay progressive neurodegeneration. Meanwhile, potential drugs in development are facing great challenges in clinical translation. Therefore, finding effective treatment for the unmet clinical needs of AD is of great economic value and social significance. In this review, we will summarize the current models and pharmacodynamics evaluation methods of anti-AD drug based on the recent studies at home and abroad, and provide reference for drug development in AD at nonclinical stage.

Recent advances in the discovery of dengue virus inhibitors / 药学学报

Dengue fever is one of the most important vector-borne human diseases caused by mosquito vector Aedes aegypti and Aedes albopictus. Dengue virus can cause dengue fever, dengue hemorrhagic fever and dengue shock syndrome. There are no approved drugs for the treatment of dengue disease so far. In this paper, combined with the latest progress in the research of anti-dengue virus, the new progress in the research of anti-dengue virus drugs was reviewed from the aspects of protease inhibitors, virus polymerase inhibitors, entry inhibitors, virus replication-related host factor inhibitors, capsid protein inhibitors and nucleic acid inhibitors.

Energy metabolism disorder and diseases: from effects to potential targets / 药学学报

Cellular energy metabolism disorder caused by dysfunction of nutrient utilization and mitochondrial damage contributes to a variety of diseases, including neurodegenerative diseases, cancer, metabolic diseases, and cardiovascular diseases. Understanding the effects of energy metabolism on diseases will help to improve our knowledge about disease etiology and may serve to develop strategies to delay disease progress. There are many compounds developed for targeting energy metabolism disorders, such as small molecules targeting the 18 kDa transporter (TSPO) for treatment of Alzheimer's disease, glucagon-like peptide-1 analogues for treatment of Parkinson's disease, inhibitors of glucose transporter 1 (GLUT1) and lactate dehydrogenase A for treatment of tumors, the fibroblast growth factors based treatment for type 2 diabetes (T2D), selective ligands of peroxisome proliferator-activated receptor (PPAR)-β/δ for treatment of cardiovascular diseases. We review here the abnormal energy metabolism of common energy metabolism disorder-related diseases, summarize the potential targets that may be used for new drug discovery, and the strategies for alleviating the disease process by improving energy metabolism.

Deep learning in drug design and discovery / 药学学报

Among various technologies used in drug design and discovery, deep learning is still in its infancy. Recently, deep learning approaches have been rapidly developed and applied to address various problems in drug discovery, including generation of virtual compound library, prediction of compound activity, metabolism and toxicity, and prediction of organic synthesis routes. Compared with the traditional machine learning methods, the prediction power of deep learning did not show significant improvement. However, proactively learning and automatically feature extraction bring advantages for deep learning approaches. Compared to first principle-based computational chemistry methods, deep learning can not be generalized because it depends on large-scale and high-quality annotated data sets. But its molecular representation with single-atom atomic environment vectors could be useful for computational chemists. As an emerging technology, deep learning, especially the unsupervised learning method that does not rely on large datasets with labels, is gradually improving. It is expected that someday deep learning method will become practical for drug discovery.

Recent advances in enzyme inhibitor screening based on mass spectrometry / 药学学报

Enzymes play crucial functional roles in all biological processes. Enzymatic inhibitors can regulate enzyme activity and may become the starting point for drug discovery. Mass spectrometry (MS) has the advantage for rapid qualitative and quantitative analyses of compounds and enzyme reactions, emerging as an important analytical tool in enzyme inhibitor screening assay for drug discovery. This review will highlight recent advances in the inhibitor screening assay using MS and related techniques, including frontier affinity chromatography, immobilized enzyme beads, ultrafiltration, surface plasmon resonance, capillary electrophoresis and microfluidic chips. The existing MS methods for screening enzyme inhibitor were divided into two types: affinity screening and activity screening.