New drugs approved by authorities are classified into two categories: new molecular entities (NME) and fixed dose combination (FDC) formulations, both of which are documented by scientific experiments and clinical trials. Complex diseases frequently possess multifactorial causes, and drugs that only focus on a single target may not achieve satisfactory results; moreover, it is difficult to achieve full optimization of the pharmacodynamics, pharmacokinetics, safety, and patient compliance for a drug. Therefore, combinatorial remedies with two (or more) drugs at a fixed dose may provide patients with better treatment options. Based upon understanding the various molecular regulation of pathological processes and principles of drug action, clinicians and pharmacologists are able to design new FDC to achieve optimum efficiency in clinical practice. In this sense the significance of FDC is no less than NME, because it is closer to clinical practice and directly meets the needs of patients. This article briefly analyzes the development of FDC from the microscopic characteristics of pathology and the molecular mechanism of drug action with influential examples.

Receptor-interacting protein kinase 1 (RIPK1) plays an essential role in regulating the necroptosis and apoptosis in cerebral ischemia-reperfusion (I/R) injury. However, the regulation of RIPK1 kinase activity after cerebral I/R injury remains largely unknown. In this study, we found the downregulation of protein arginine methyltransferase 1 (PRMT1) was induced by cerebral I/R injury, which negatively correlated with the activation of RIPK1. Mechanistically, we proved that PRMT1 directly interacted with RIPK1 and catalyzed its asymmetric dimethylarginine, which then blocked RIPK1 homodimerization and suppressed its kinase activity. Moreover, pharmacological inhibition or genetic ablation of PRMT1 aggravated I/R injury by promoting RIPK1-mediated necroptosis and apoptosis, while PRMT1 overexpression protected against I/R injury by suppressing RIPK1 activation. Our findings revealed the molecular regulation of RIPK1 activation and demonstrated PRMT1 would be a potential therapeutic target for the treatment of ischemic stroke.

Small molecule drugs comprise multi-dimensional features, and drug creation has to meet requirements such as safety, effectiveness, stability, controllability, and patient compliance. These attributes can be summarized as pharmacological activity and druglikeness, which are implicit in the chemical structure of the drug. Pharmacological activity and adverse reactions are caused by the interaction between drug molecules and on-target or off-target protein. The microstructure of the drug determines the activity/toxicity intensity and selectivity. Pharmacokinetic and physicochemical properties are related to the macroscopic properties of the drug, and the microstructure and macroscopic properties are intertwined and integrated into the molecular structure. Conception and construction of bifunctional molecules are one of routes to achieve "unification of micro and macro" and structurally straighten out the relationship between pharmacodynamics-pharmacokinetics, drug efficacy-adverse reactions (selectivity). This article takes drugs that have been successfully marketed or under clinical trials as examples to explain the structural characteristics of bifunctional molecules from the viewpoint of medicinal chemistry. The productive technical methods include antibody-drug conjugate, proteolysis-targeting chimeras, molecular glues, peptide modifications, and so on. In addition, this overview also classifies covalently binding drugs, transition-state analogs, and prodrugs into the category of bifunctional molecules, emphasizing the importance of bifunctional groups in molecular design and structure optimization.

The chemically induced proximity (CIP) in biological realm is an important way to maintain the function of organism and cells. In recent years, CIP has been paid attention to and applied in the field of bio-medicines. Molecular glue and PROTAC are widely investigated for the treatment of tumors and immunopathy. Based upon the CIP principle molecular glue and PROTAC promote two proteins to approach each other, induce the complementary binding to triads, and then degrade the target protein or regulate functions. Different from conventional drugs, molecular glue acts as a catalyst, which induces two proteins to approach, bind and ubiquitinate, without taking part in the subsequent degradation process, so it can theoretically function in an infinite cycle. In this article, the development process, structural characteristics and functional characteristics of some molecular glues in clinical trials are briefly discussed from the viewpoint of medicinal chemistry.

Artificial intelligence-aided drug discovery (AIDD) is a new version of computer-aided drug discovery (CADD). AIDD is featured in significantly promoting the performance of conventional CADD. AI markedly enhances the learning ability of CADD. In the 1960s, CADD was established from conventional QSAR approaches, which mainly used regression approaches to derive substructure-activity relationship for compounds with a common scaffold, and guide drug molecular design, figure out the binding features of drugs, and identify potential drug targets. Since the 1990s, structural biology has provided three-dimensional structures of drug targets, enabling drug discovery based on target structure (SBDD), fragment-based drug discovery (FBDD), and structure-based virtual screening (SBVS) with CADD approaches. In the past 30 years, many first in class (FIC) and best in class (BIC) drugs were discovered with CADD. Now, AIDD will further revolutionize CADD by reducing human interventions and mining big chemical and biological data. It is expected that AIDD will significantly enhance the abilities of CADD, virtual screening and drug target identification. This article tries to provide perspectives of CADD and AIDD in medicinal chemistry with case studies.

Although small molecule drugs (SMD) are still mainstream for the treatment of diseases, large molecule biologicss of many advantages, pose a challenge to the further discovery and use of SMD. The advantages of SMD are the convenience of oral administration and good patient compliance. However, the challenge with SMD is to integrate the PD, PK, selectivity and safety into a chemical structure. Because of their small size and surface area they often bind to various proteins, and off-target actions can cause adverse reactions. In this sense, selectivity is critical. Based upon target as the core to construct a chemical structure, it is necessary to consider the requirements of all the attributes, but achievement of the full-dimensional optimization is difficult. Modern drug discovery has been greatly enhanced by molecular biology and structural biology, and new strategies and technologies have emerged, which have created many successful medicines. For example, under the guidance of structural biology, covalent binding drugs connect moderate "electrophilic warheads" to the appropriate positions of molecules, and upon binding to their targets the electrophiles are irreversibly linked to the target by covalent bonds. Molecular biology can be directly applied to the development of antibody-coupled drugs (ADC). The antibody (A) acts as a carrier and a guide (for PK), and carries toxic molecules (D) into cancer cells, thus playing a killing role (for PD). The separate pharmacodynamic and pharmacokinetic entities are coupled (C) by linkers. PROTACs are also bifunctional molecules, which recruit a target protein and ubiquitin ligase E3 to form a ternary complex, which then acts as a catalyst to ubiquitinate the target protein and lead to degradation by the proteasome. In addition, in recent years, the combination of two fixed-dose drugs has improved selectivity, safety, and long-term benefit with many severe diseases, and can be regarded as an innovative strategy of physical combination. This review discusses some successful examples to briefly present the principles from the perspective of medicinal chemistry and therapeutic application.

The binding of small molecule drugs to targets is mostly through non-covalent bonds, and hydrogen bond, electrostatic, hydrophobic and van der Waals interactions function to maintain the binding force. The more these binding factors lead to strong bindings and high activities. However, it is often accompanied by the increase of molecular size, resulting in pharmacokinetic problems such as membrane penetration and absorption, as well as metabolism, which ultimately affects the drug success. Fragment-based drug discovery (FBDD) is to screen high-quality fragment library to find hits. Combine with structural biology, FBDD generates lead compounds by means of fragment growth, linking and fusion, and finally drug candidates by the optimization operation. During the value chain FBDD is closely related to structure-based drug discovery (SBDD). In this paper, the principle of FBDD is briefly described by several launched drugs.

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.

OBJECTIVE: To explore the characteristics and clinical phenotypes of rheumatoid arthritis (RA) and provide the basis for further understanding, interventions and outcomes of this disease. METHODS: RA patients attended at Peking University People's Hospital from 2018 to 2021 were enrolled in the study. Data collection included demographic data, the sites and numbers of joints involved, extra-articular manifestations (EAM), comorbidities and laboratory variables. Statistical and bioinformatical analysis was performed to establish clinical subtypes by clustering analysis based on the type of joint involved, EAM involvement and other autoimmune diseases overlapped. The characteristics of each subtype were analyzed. RESULTS: A total of 411 patients with RA were enrolled. The mean age was (48.84±15.17) years, and 346 (84.2%) were females. The patients were classified into 4 subtypes: small joint subtype (74, 18.0%), total joint subtype (154, 37.5%), systemic subtype (100, 24.3%), and overlapping subtype (83, 20.2%). The small joint subtype had no medium or large joint involvement, and 35.1% had systemic involvement. The erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) levels and platelet count (PLT) were lower than those in other subtypes, and the rates of positive rheumatoid factors (RF-IgA and RF-IgG) were significantly higher in the small joint subtype. The total joint subtype had both large and small joint involvement but no systemic involvement. The rate of morning stiffness and positive antinuclear antibodies (ANA) in this subtype were lower than those in other subtypes. In the systemic subtype, interstitial lung disease and secondary Sjögren syndrome were the most common systemic involvements, with prominent levels of disease activity score 28-joint count (DAS28-ESR and DAS28-CRP). The overlapping subtype was commonly combined with Hashimoto's thyroiditis or primary Sjögren syndrome. Female in the overlapping subtype was more common than in other subtypes. This subtype was characterized by hyperglobulinemia, hypocomplementemia and high rate of positive ANA, especially spotting type. CONCLUSION Based on the clinical features, RA patients could be classified into 4 subtypes: small joint subtype, total joint subtype, systemic subtype, and overlapping subtype. Each subtype had its own clinical characteristics. They help for further understanding and a more individualized treatment strategy of RA.
Female ; Male ; Humans ; Cross-Sectional Studies ; Sjogren's Syndrome ; Rheumatoid Factor ; Arthritis, Rheumatoid ; Blood Sedimentation ; Phenotype

Pharmacological activity and drug likeness depend in principle upon the microscopic structure and macroscopic properties of drugs, which reside in their molecular structures. By means of medicinal chemistry the evolution of an active compound to a novel drug (NME) essentially makes the two pillars coexistence in one chemical structure, which either could merge as an intrinsic structure or connect from external fragments to each other with covalent bonds. Since the new millennium the advance in biology provides several knowledge and technologies, for example humanized monoclonal antibody, proteasome-ubiquitin system, allosteric modulation, natural macromolecules, structural biology, etc., for innovation of novel medicines. Taking several examples on marketed drugs or drug candidates in clinical trials, this article tries to concisely illustrate R & D conception of biology-driven drug design.