花时间整理了药物设计学课件中英文，并使用ChatGPT进行了翻译并汇总成了文档，希望对你有用！PDF获取

第一章

Drug Design - IUPAC

• Drug design includes not only ligand design, but also pharmacokinetics and toxicity, which are mostly beyond the possibilities of structure- and/or computer-aided design. Nevertheless, appropriate chemometric tools, including experimental design and multivariate statistics, can be of value in the planning and evaluation of pharmacokinetic experiments and results, and toxicological studies.

• Drug design is most often used instead of the correct term 'Ligand Design'.

药物设计 - IUPAC

• 药物设计不仅包括配体设计，还涉及药代动力学和毒性，这些大多超出了结构和/或计算机辅助设计的范围。然而，适当的化学计量学工具，包括实验设计和多变量统计学，在药代动力学实验和结果的规划与评估中可以发挥重要作用，并在毒理学研究中也具有价值。

• 药物设计通常作为'配体设计'的替代术语使用。

New Molecular Entity (NME)

A new molecular entity (NME) is a new drug or biological product that contains a new active moiety or is structurally different from previously approved products.

新化学实体

新化学实体（NME）是指一种新药或生物制品，包含一种新的活性部分，或其结构与先前批准的产品有所不同。

第二章

Target-based Drug Discovery

Target-based drug discovery can exploit numerous approaches (including crystallography, computational modeling, genomics, biochemistry, and binding kinetics) to uncover exactly how a drug interacts with the target of interest, enabling:

  1. Development of the structure-activity relationship (SAR) (the relationship between the structure and biological activity of a molecule);
  2. Development of biomarkers;
  3. Discovery of future therapeutics that act at the specific target of interest.

靶向药物发现

靶向药物发现可以利用多种方法（包括晶体学、计算建模、基因组学、生物化学和结合动力学）来揭示药物与目标的相互作用，进而实现：

  1. 结构-活性关系（SAR）的开发（分子结构与生物活性之间的关系）；
  2. 生物标志物的开发；
  3. 发现未来能够在特定靶点上发挥作用的治疗药物。

Magic Bullet Concept

Drugs that go straight to their intended cell-structural targets. Targeted medicine should, in theory, efficaciously attack pathogens yet remain harmless in healthy tissues.

神奇子弹概念

药物直接作用于其预定的细胞结构靶点。靶向药物理论上应能够有效攻击病原体，同时对健康组织无害。

Drug Receptor

A drug receptor is a specialized target macromolecule that binds a drug and mediates its pharmacological action. These receptors may be enzymes, nucleic acids, or specialized membrane-bound proteins. The formation of the drug-receptor complex leads to a biological response.

药物受体

药物受体是与药物结合并介导其药理作用的特定靶向大分子。这些受体可以是酶、核酸或特殊的膜结合蛋白。药物-受体复合物的形成引发生物学反应。

Drug Target

• A target is usually a single gene, gene product, or molecular mechanism that has been identified on the basis of genetic analysis or biological observations. They will be divided into two classes: genetic or mechanistic targets.
• Genetic targets represent genes or gene products that, in specific diseases, have been found to carry mutations (e.g., the familial forms of Alzheimer's Disease) or that confer a higher disease risk (e.g., predisposing the individual to develop schizophrenia or depression).
• Mechanistic targets represent receptors, genes, enzymes, and so on that usually are not genetically different from the normal population. These latter targets originate from biological processes.

药物靶点

• 靶点通常是根据基因分析或生物学观察确定的单一基因、基因产物或分子机制。靶点可分为两类：遗传靶点或机制靶点。
• 遗传靶点代表那些在特定疾病中被发现携带突变的基因或基因产物（如家族性阿尔茨海默病），或代表那些赋予较高疾病风险的基因（如使个体易患精神分裂症或抑郁症）。
• 机制靶点代表通常与正常人群没有基因差异的受体、基因、酶等。这些靶点源自生物学过程。

Properties of an Ideal Drug TargetGashaw, I., Ellinghaus, P., Sommer, A., & Asadullah, K. (2012). What makes a good drug target?. Drug Discovery Today, 17, S24-S30. doi: 10.1016/j.drudis.2011.12.008

  1. The target has a confirmed role in the pathophysiology of a disease and/or is disease-modifying.
  2. Target expression is not evenly distributed throughout the body.
  3. The target’s 3D structure is available to assess druggability.
  4. The target is easily ‘assayable’, enabling high throughput screening.
  5. The target possesses a promising toxicity profile, and potential adverse effects can be predicted using phenotypic data.
  6. The proposed target has a favorable intellectual property position.

理想药物靶点的特性Gashaw, I., Ellinghaus, P., Sommer, A., & Asadullah, K. (2012). What makes a good drug target?. Drug Discovery Today, 17, S24-S30. doi: 10.1016/j.drudis.2011.12.008

  1. 靶点在疾病的病理生理学中具有确凿的作用，和/或具有改变疾病进程的作用。
  2. 靶点在体内的表达并非均匀分布。
  3. 靶点的三维结构可用，以评估其作为药物靶点的可行性。
  4. 靶点易于进行检测，支持高通量筛选。
  5. 靶点具有有前景的毒性特征，潜在的不良反应可通过表型数据预测。
  6. 提议的靶点具有有利的知识产权位置。

Druggable Target

A ‘druggable’ target is a protein, peptide, or nucleic acid with activity that can be modulated by a drug, which can consist of a small molecular weight chemical compound (SMOL) or a biologic (BIOL), such as an antibody or a recombinant protein.

可药物化靶点

“可药物化”的靶点是指具有活性的蛋白质、肽或核酸，这些活性可以通过药物进行调节，药物可以是小分子化学化合物（SMOL）或生物制品（BIOL），如抗体或重组蛋白。

Target Identification

Target identification is a first and foremost step in drug discovery. It is the process of identifying the direct molecular targets of small molecules, such as nucleic acids and proteins. Target identification can be approached by computational methods, direct biochemical methods, and genetic interactions.

靶点识别

靶点识别是药物发现中的首要步骤。它是识别小分子直接作用的分子靶标的过程，这些靶标包括核酸和蛋白质。靶点识别可以通过计算方法、直接生化方法和遗传相互作用来进行。

Obesity and Overweight

Key Facts

  • In 2022, 1 in 8 people in the world were living with obesity.
  • Worldwide adult obesity has more than doubled since 1990, and adolescent obesity has quadrupled.
  • In 2022, 2.5 billion adults (18 years and older) were overweight. Of these, 890 million were living with obesity.
  • In 2022, 43% of adults aged 18 years and over were overweight and 16% were living with obesity.
  • In 2022, 37 million children under the age of 5 were overweight.
  • Over 390 million children and adolescents aged 5–19 years were overweight in 2022, including 160 million who were living with obesity.
  • Overweight and obesity result from an imbalance of energy intake (diet) and energy expenditure (physical activity).

肥胖与超重

关键事实

  • 2022年，全球每8人中就有1人患有肥胖症。
  • 全球成年肥胖率自1990年以来已增加超过一倍，青少年肥胖率增长了四倍。
  • 2022年，全球有25亿成年人（18岁及以上）超重，其中8.9亿人患有肥胖症。
  • 2022年，43%的成年人（18岁及以上）超重，16%的人患有肥胖症。
  • 2022年，3700万5岁以下儿童超重。
  • 2022年，全球有超过3.9亿5至19岁的儿童和青少年超重，其中1.6亿人患有肥胖症。
  • 超重和肥胖是由于能量摄入（饮食）和能量消耗（体育活动）之间的不平衡所导致的。

Cancer

Cancer is a large group of diseases that can start in almost any organ or tissue of the body when abnormal cells grow uncontrollably, go beyond their usual boundaries to invade adjoining parts of the body and/or spread to other organs. The latter process is called metastasizing and is a major cause of death from cancer.

癌症

癌症是一个包含多种疾病的大类，它可以在几乎任何器官或组织中发源，当异常细胞失控生长、突破常规边界侵入邻近的身体部位和/或扩散到其他器官时，就会发生癌症。这个过程叫做转移，且是癌症致死的主要原因。

Cancer Prevention

  • Between 30% and 50% of cancer deaths could be prevented by modifying or avoiding key risk factors and implementing existing evidence-based prevention strategies.
  • Avoid tobacco use, including cigarettes and smokeless tobacco.
  • Maintain a healthy weight.
  • Eat a healthy diet with plenty of fruits and vegetables.
  • Exercise regularly.
  • Limit alcohol use.
  • Practice safe sex.
  • Get vaccinated against hepatitis B and human papillomavirus (HPV).
  • Reduce exposure to ultraviolet radiation.
  • Get regular medical care.
  • Prevent unnecessary ionizing radiation exposure (e.g., minimize occupational exposure, ensure safe and appropriate medical use of radiation in diagnosis and treatment).
  • Avoid urban air pollution and indoor smoke from household use of solid fuels.
  • Some chronic infections are also risk factors for cancer.

癌症预防

  • 通过修改或避免关键风险因素，并实施现有的基于证据的预防策略，30%到50%的癌症死亡是可以预防的。
  • 避免使用烟草，包括香烟和无烟烟草。
  • 保持健康体重。
  • 饮食健康，多吃水果和蔬菜。
  • 定期锻炼。
  • 限制酒精摄入。
  • 进行安全性行为。
  • 接种乙型肝炎疫苗和人乳头瘤病毒（HPV）疫苗。
  • 减少紫外线辐射的暴露。
  • 定期接受医疗护理。
  • 防止不必要的电离辐射暴露（例如，减少职业暴露，确保在诊断和治疗中安全、适当地使用辐射）。
  • 避免城市空气污染和使用固体燃料的室内烟雾。
  • 一些慢性感染也是癌症的风险因素。

A Family of Receptors with PTK Activity

Tyrosine-specific kinases phosphorylate tyrosine amino acid residues, and like serine/threonine-specific kinases, they are used in signal transduction. They act primarily as growth factor receptors and in downstream signaling from growth factors:

  1. Platelet-derived growth factor receptor (PDGFR)
  2. Epidermal growth factor receptor (EGFR)
  3. Insulin receptor and insulin-like growth factor 1 receptor (IGF1R)
  4. Stem cell factor (SCF) receptor (c-kit)
  5. Vascular endothelial growth factor receptor (VEGFR)
  6. Fibroblast growth factor receptors (FGFR)

具有PTK活性的受体家族

酪氨酸特异性激酶磷酸化酪氨酸氨基酸残基，像丝氨酸/苏氨酸特异性激酶一样，它们参与信号转导。它们主要作为生长因子受体，并在生长因子的下游信号传导中发挥作用：

  1. 血小板衍生生长因子受体（PDGFR）
  2. 表皮生长因子受体（EGFR）
  3. 胰岛素受体和胰岛素样生长因子1受体（IGF1R）
  4. 干细胞因子（SCF）受体（c-kit）
  5. 血管内皮生长因子受体（VEGFR）
  6. 成纤维生长因子受体（FGFR）

第三章

Chemoinformatics

Chemoinformatics is a large scientific discipline that deals with the storage, organization, management, retrieval, analysis, dissemination, visualization, and use of chemical information. Chemoinformatics techniques are used extensively in drug discovery and development.

化学信息学

化学信息学是一个涵盖存储、组织、管理、检索、分析、传播、可视化和使用化学信息的广泛科学领域。化学信息学技术在药物发现与开发中得到广泛应用。

Bioinformatics

Bioinformatics is a hybrid science that links biological data with techniques for information storage, distribution, and analysis to support multiple areas of scientific research, including biomedicine.

生物信息学

生物信息学是一门将生物数据与信息存储、分发和分析技术相结合的交叉学科，旨在支持多个科学研究领域，包括生物医学。

第四章

Structure-based drug design (SBDD) is the design and optimization of a chemical structure with the goal of identifying a compound suitable for clinical testing — a drug candidate. It is based on knowledge of the drug’s three-dimensional structure and how its shape and charge cause it to interact with its biological target, ultimately eliciting a medical effect.
• (Source: https://www.nature.com/subjects/structure-based-drug-design)

基于结构的药物设计 (SBDD) 是一种化学结构的设计和优化，目的是鉴定出适合临床测试的化合物——药物候选物。它基于对药物三维结构的了解，以及药物的形状和电荷如何使其与生物靶标相互作用，最终引发医疗效应。
• （来源于https://www.nature.com/subjects/structure-based-drug-design）

第五章

ADMET: Ideal Properties of Drugs

  • Absorption - Passes through the gastrointestinal tract into the bloodstream
  • Distribution - Reaches the target tissue (e.g., blood-brain barrier)
  • Metabolism - Not readily metabolized
  • Excretion - Not readily secreted
  • Toxicity - Not toxic to other cells or tissues

ADMET：理想的药物特性

  • 吸收 - 能通过胃肠道进入血液
  • 分布 - 到达靶组织（例如血脑屏障）
  • 代谢 - 不易被代谢
  • 排泄 - 不易被分泌
  • 毒性 - 对其他细胞或组织无毒

Drug-likeness involves consideration of how properties of chemicals, such as lipophilicity, compare with those of approved drugs.

药物相似性 涉及对化学物质属性的考虑，例如脂溶性，并将其与已批准药物的属性进行比较。

第六章

Combinatorial chemistry is a laboratory technique in which millions of molecular constructions can be synthesized and tested for biological activity.

组合化学 是一种实验室技术，能够合成并测试数百万种分子结构的生物活性。

High content screening (HCS) combines the efficiency of high-throughput techniques with the ability of cellular imaging to collect quantitative data from complex biological systems.

高内容筛选（HCS） 将高通量技术的效率与细胞成像的能力相结合，从复杂的生物系统中收集定量数据。

As an alternative or complementary approach to high-throughput screening assays, virtual screening is an efficient method to identify drug candidates in silico from large chemical compound databases. Its usefulness has been verified by current applications that successfully retrieved hit and lead identifications against various disease targets.

作为高通量筛选实验的替代或补充方法，虚拟筛选 是一种高效的方法，通过计算机模拟从大型化学化合物数据库中识别药物候选物。其有效性已经通过当前应用得到了验证，这些应用成功地筛选出针对各种疾病靶标的命中物和领先化合物。

The last step in the biosynthesis of androgens (for example, testosterone) involves two key reactions that occur sequentially and are both catalyzed by a single enzyme, the cytochrome P450 monooxygenase 17α hydroxylase/17,20-lyase (CYP17 or 17-lyase). Ketoconazole, an antifungal agent that is also a modest CYP17 inhibitor, has been used clinically for the treatment of PC. However, ketoconazole has now been withdrawn from use because of liver toxicity and other side effects due mainly to its inhibition of other CYP enzymes.

雄激素（例如睾酮）生物合成的最后一步涉及两个关键反应，这些反应依次发生，并且都由同一酶——细胞色素P450单加氧酶17α羟化酶/17,20-裂解酶（CYP17或17-裂解酶）催化。克霉唑是一种抗真菌剂，也是CYP17的适度抑制剂，曾用于临床治疗PC。然而，克霉唑现已停止使用，因为其对肝脏的毒性和其他副作用，主要是由于它抑制了其他CYP酶。

Common feature-based (Catalyst/HipHop) pharmacophore model of azole steroid-based human CYP17 inhibitors. The model contains five features: three hydrophobes (cyan) and two hydrogen bond acceptors (green).

基于共同特征的（Catalyst/HipHop）药效团模型，适用于类唑类类固醇的人类CYP17抑制剂。 该模型包含五个特征：三个疏水基团（青色）和两个氢键受体（绿色）。

Alignment of common-feature pharmacophore model with training set CYP17 inhibitors.

共同特征药效团模型与训练集CYP17抑制剂的对接。

第七章

第一节

Representation of Protein Targeting Strategies

  1. Non-covalent Inhibition

    • Binding Forces: Electrostatic interactions; Van der Waals interactions; Hydrogen bonds; Hydrophobic effect; Charge-transfer interactions
    • Features: Reversible; Equilibrium-binding mechanism

  2. Irreversible Covalent Inhibition

    • Binding Forces: Covalent bond + Non-covalent interaction
    • Features: Irreversible; Non-equilibrium-binding mechanism

  3. Reversible Covalent Inhibition

    • Binding Forces: Covalent bond + Non-covalent interaction
    • Features: Covalent but reversible; Equilibrium-binding mechanism

蛋白质靶向策略的表现

  1. 非共价抑制

    • 结合力： 静电相互作用；范德华力相互作用；氢键；疏水效应；电荷转移相互作用
    • 特点： 可逆；平衡结合机制

  2. 不可逆共价抑制

    • 结合力： 共价键 + 非共价相互作用
    • 特点： 不可逆；非平衡结合机制

  3. 可逆共价抑制

    • 结合力： 共价键 + 非共价相互作用
    • 特点： 共价但可逆；平衡结合机制

Clopidogrel:
Covalently bound to P2Y purinergic receptor 12.

Neratinib:
Forms a covalent interaction with the conserved cysteine residue (Cys 773 in EGFR and Cys-805 in HER2).

氯吡格雷（Clopidogrel）：
与P2Y嘌呤受体12形成共价结合。

奈拉替布（Neratinib）：
与保守的半胱氨酸残基（EGFR中的Cys 773和HER2中的Cys-805）形成共价相互作用。

Prevalence of Covalent Drugs

  1. 19/74Of 74 enzymes that are inhibited by marketed drugs, 19 are irreversibly inhibited via covalent modification.
  2. 30%
    ~30% of marketed drugs act via a covalent mechanism of action, although the majority of those were not originally designed as covalent drugs.

共价药物的流行程度

  1. 19/74在74种被市场药物抑制的酶中，有19种通过共价修饰被不可逆地抑制。
  2. 30%
    大约30%的市场药物通过共价作用机制发挥作用，尽管其中大多数药物最初并非作为共价药物设计。

Advantages of Covalent Drugs

  1. Improved Biochemical EfficiencyAs competition with endogenous substrates is reduced, covalent drugs often exhibit enhanced biochemical efficiency.
  2. Lower, Less Frequent DosingThis leads to a lower overall patient burden, as drugs can be dosed less frequently.
  3. Dissociation of Pharmacokinetics from Pharmacodynamics (PD)Since pharmacodynamics (PD) is now dependent on protein re-synthesis, this allows for quicker clearance of compounds, making them more acceptable and resulting in lower systemic drug exposure.
  4. Potential Prevention of Drug Resistance
    Continuous target suppression by covalent binding can help prevent the emergence of drug resistance.

共价药物的优点

  1. 提高生化效率由于减少了与内源性底物的竞争，共价药物通常表现出更高的生化效率。
  2. 较低且不频繁的给药这导致整体患者负担减少，因为药物可以较少频繁地给药。
  3. 药代动力学与药效学（PD）的分离由于药效学现在依赖于蛋白质的再合成，这使得药物能迅速清除，从而使药物更易接受，并导致更低的全身药物暴露。
  4. 潜在的药物耐药性预防
    由于共价结合持续抑制靶标，可能有助于防止药物耐药性的产生。

Disadvantages of (or Concerns About) Covalent Drugs

  1. Balance Between Reactivity and SpecificityIt is difficult to strike the right balance between reactivity and specificity. There is a high risk if a covalent inhibitor lacks specificity, leading to off-target effects.

    • Example: Hepatotoxicity of acetaminophen, where the active metabolite covalently binds to microsomal proteins.
  2. Potential ImmunogenicityProtein-inhibitor adducts may trigger an immune response, leading to allergic reactions or drug hypersensitivity.
  3. Not Optimal for Certain Targets
    Covalent drugs are not ideal for targets where the mechanism of action requires short residence time, transient inhibition, or partial inhibition.

共价药物的缺点（或关注点）

  1. 反应性与特异性之间的平衡问题很难在反应性和特异性之间找到合适的平衡。如果共价抑制剂缺乏特异性，可能会导致高风险的非特异性作用。

    • 例子： 对乙酰氨基酚的肝毒性，活性代谢物与微粒体蛋白共价结合。
  2. 潜在的免疫原性蛋白质-抑制剂加合物可能引发免疫反应，导致过敏反应或药物超敏反应。
  3. 不适用于某些靶点
    共价药物对于那些机制需要短时间作用、暂时性抑制或部分抑制的靶点并不理想。

Targeted Covalent Inhibitors (TCIs)

  • A targeted covalent inhibitor (TCI) is designed such that the initial, reversible association between the ligand and the target is followed by the formation of a covalent bond between an electrophile on the ligand (warhead) and a nucleophilic center in the protein.
  • While this approach offers a variety of potential benefits, including high potency and extended duration of action, concerns over the possible toxicological consequences of protein haptenization have hindered the development of the TCI concept.
  • Recently, strategies to mitigate the risk of serious adverse reactions to this new class of agents have emerged, stimulating interest in the field and leading to the authorization of the first cadre of TCIs to be marketed.
  • The covalent inhibitor approach is rapidly gaining acceptance as a valuable tool in drug discovery and is poised to make a significant impact on the design of enzyme inhibitors and receptor modulators.

靶向共价抑制剂（TCIs）

  • 靶向共价抑制剂（TCI）的设计使得配体与靶标之间最初的可逆结合后，会形成配体上的亲电基团（战斗头）与蛋白质中的亲核中心之间的共价键。
  • 尽管这种方法提供了多种潜在的益处，包括高效能和延长作用时间，但关于蛋白质载体化可能带来的毒理学后果的担忧，限制了TCI概念的发展。
  • 最近，为减轻对这一新类药物的严重不良反应的风险，已出现了新的策略，从而激发了该领域的兴趣，并促使第一批TCI药物的上市授权。
  • 共价抑制剂方法正在迅速获得认可，成为药物发现中的重要工具，并有望对酶抑制剂和受体调节剂的设计产生重大影响。

Theoretical benefits of TCIs

• (i) an extended duration of therapeutic action that is determined by the target protein turnover rate and not necessarily by drug half-life,
• (ii) a lower therapeutic dose owing to greater pharmacological potency,
• (iii) lower risk of off-target binding and associated adverse events,
• (iv) reduced drug-drug interaction (DDI) liability due to high selectivity and low dose.

TCIs的理论益处

• (i) 由靶标蛋白的更替速率决定的较长疗效持续时间，而不一定由药物半衰期决定，
• (ii) 由于更高的药理效能，较低的治疗剂量，
• (iii) 较低的脱靶结合及相关不良事件的风险，
• (iv) 由于高选择性和低剂量，减少药物间相互作用（DDI）的风险。

Requirement for developing covalent drugs

• 1. Nucleophilic species in noncatalytic amino acid residue located nearby the active site
• eg. -OH in serine; -SH in cysteine
• More than 200 of 518 kinases have such a cysteine residue, which could be targeted by an ATP binding site inhibitor (Zhang, J. Nat. Rev. Cancer, 2009, 9, 28-39.)
• 2. Highly electrophilic species incorporated in the inhibitor
• eg. α-haloketone, α,β-unsaturated ketone, fluorophosphonate, cyanamide

开发共价药物的要求

• 1. 位于靠近活性位点的非催化氨基酸残基中的亲核物种
• 例如：丝氨酸的-OH；半胱氨酸的-SH
• 518种激酶中有超过200种含有这样的半胱氨酸残基，可以被ATP结合位点抑制剂靶向（Zhang, J. Nat. Rev. Cancer, 2009, 9, 28-39.）
• 2. 抑制剂中含有高度电负性的物种
• 例如：α-卤代酮、α,β-不饱和酮、氟磷酸酯、氰胺

Design an irreversible covalent inhibitor

• Imatinib (Gleevec)
• Developed by Novartis; Approved by FDA in 2001
A tyrosine-kinase inhibitor treating multiple cancers, notably Ph+-CML (Philadelphia chromosome-positive chronic myelogenous leukemia)
• Designed to selectively target Abelson tyrosine kinase (ABL)
• But also targets the mast/stem cell growth factor receptor (KIT) and the platelet-derived growth factor receptor (PDGFR)

设计不可逆共价抑制剂

• 伊马替尼（Gleevec）
• 由诺华公司开发；2001年获得FDA批准
一种酪氨酸激酶抑制剂，治疗多种癌症，尤其是Ph+-CML（费城染色体阳性慢性髓性白血病）
• 设计上选择性地靶向Abelson酪氨酸激酶（ABL）
• 但也靶向肥大细胞/干细胞生长因子受体（KIT）和血小板衍生生长因子受体（PDGFR）

Design irreversible covalent inhibitors

Conclusion:

  1. The structural analysis described herein provides a thorough landscape of cysteine positions that can be exploited for irreversible inhibition. Taking into account the different conformations of kinases has revealed previously unrecognized opportunities.
  2. The identification of an inhibitor that discriminates between ABL and KIT/PDGFRs illustrates the opportunities to enhance selectivity by harnessing unconserved cysteine residues.
  3. Although the selective targeting of ABL was not achieved, the selectivity of Imatinib was improved.

设计不可逆共价抑制剂

结论：

  1. 本文所述的结构分析提供了可用于不可逆抑制的半胱氨酸位置的详细概况。考虑到激酶的不同构象，揭示了此前未曾认识到的机会。
  2. 识别出能够区分ABL与KIT/PDGFR的抑制剂，展示了通过利用未保守的半胱氨酸残基来增强选择性的机会。
  3. 尽管未能实现对ABL的选择性靶向，但伊马替尼的选择性得到了改善。

Molecular Glues (分子胶)

• Molecular glues are a class of small molecule compounds that can induce or stabilize the interaction between proteins.
• If one of the proteins is an ubiquitin ligase, molecular glue can cause another protein to undergo ubiquitin modification and degradation through the proteasome pathway, which is similar to PROTAC.
• However, these molecules are classified as ligands for E3 ligase as functional molecules in subsequent classification.
• Older drugs, thalidomide, lenalidomide, and pomalidomide, together with CC-90009 and CC-92480, all belong to this category.

分子胶

• 分子胶是一类能够诱导或稳定蛋白质之间相互作用的小分子化合物。
• 如果其中一个蛋白质是泛素连接酶，分子胶可以导致另一个蛋白质通过蛋白酶体通路进行泛素修饰和降解，这与PROTAC类似。
• 然而，这些分子在后续分类中被归类为E3连接酶的配体作为功能分子。
• 老药，如沙利度胺、来那度胺和泊马度胺，以及CC-90009和CC-92480，都属于这一类别。

PROTAC vs Classic Protein Modulator

Limitations of traditional small molecule inhibitors

  1. Difficult to identify inhibitors based on undruggable targets
  2. Inhibition induced target mutation and accumulation lead to drug resistance
  3. High dosage and low selectivity induces abnormal response
  4. Drug metabolism results in low effect

Advantages of PROTACs

  1. The active site of the target of interest (TOI) is not indispensable.
  2. PROTACs directly degrade the target.
  3. PROTACs may effectively induce protein degradation even at low concentrations.
  4. E3 ligase ligand increases the selectivity.
  5. The recovery of biological function relies on the resynthesis of the protein.

PROTAC vs 经典蛋白质调节剂

传统小分子抑制剂的局限性

  1. 难以基于不可药物化靶标识别抑制剂
  2. 抑制导致靶标突变和积累，从而引发耐药性
  3. 高剂量和低选择性诱导异常反应
  4. 药物代谢导致效果低下

PROTAC的优势

  1. 目标蛋白（TOI）的活性位点并非必不可少
  2. PROTAC直接降解目标蛋白
  3. 即使在低浓度下，PROTAC也能有效诱导蛋白降解
  4. E3连接酶配体增加了选择性
  5. 生物学功能的恢复依赖于蛋白质的重新合成

Linkers of PROTACs

• Basic Function: Connecting an E3 ligase-recruiting moiety and a TOI ligand to form a tertiary complex of PROTAC, E3 ligase, and TOI.• Important: The connecting position should be far from the interaction region.• Other Functions:

  • Linker length modulates the activity and selectivity.
  • Linker type modulates the PROTAC's physico-chemical properties, impacting water solubility and cell permeability.• Common Linkers:
  • Polyethylene glycol (PEG)
  • Pure lipophilic alkyl chains
  • Rigid linkers through heterocyclic scaffolds such as piperidine and piperazine.

PROTAC的连接链

• 基本功能: 连接E3连接酶招募基团和目标蛋白配体，形成PROTAC、E3连接酶和目标蛋白的三元复合物。• 重要: 连接位置应远离相互作用区域。• 其他功能:

  • 连接链的长度调节活性和选择性。
  • 连接链的类型调节PROTAC的理化性质，进而影响水溶性和细胞渗透性。• 常见连接链:
  • 聚乙烯醇（PEG）
  • 纯疏水性烷基链
  • 通过含氮杂环骨架（如哌啶和哌嗪）形成的刚性连接链。

Design

• No crystal structure of AR (Androgen Receptor) in an antagonist conformation complexed with an AR antagonist is available.
• FDA-approved AR antagonist, Enzalutamide, was used to construct PROTACs.
• The anchor point is defined by structure-activity relationship (SAR).

设计

• 目前没有AR（雄激素受体）与AR拮抗剂复合物的拮抗构象晶体结构。
• FDA批准的AR拮抗剂恩杂鲁胺（Enzalutamide）被用于构建PROTAC。
• 锚点由结构-活性关系（SAR）确定。

第二节

Artificial Intelligence

• Artificial intelligence (AI): 智能主体可以理解数据及从中学习，并利用知识实现特定目标和任务的能力。
• A system’s ability to correctly interpret external data, to learn from such data, and to use those learnings to achieve specific goals and tasks through flexible adaptation.
• Artificial intelligence (AI) is the theory and development of computer systems capable of performing tasks that historically required human intelligence, such as recognizing speech, making decisions, and identifying patterns.
• AI is an umbrella term that encompasses a wide variety of technologies, including machine learning, deep learning, and natural language processing (NLP).

人工智能

• 人工智能（AI）：智能主体可以理解数据及从中学习，并利用知识实现特定目标和任务的能力。
• 系统正确解读外部数据、从中学习，并通过灵活的适应性利用这些学习来实现特定目标和任务的能力。
• 人工智能（AI） 是计算机系统理论与开发，能够执行历史上需要人类智慧的任务，如语音识别、决策制定和模式识别。
• AI是一个总称，涵盖了广泛的技术，包括机器学习、深度学习和自然语言处理（NLP）。

Antimicrobial Resistance

• Key Facts

  • Antimicrobial resistance (AMR) is one of the top global public health and development threats. It is estimated that bacterial AMR was directly responsible for 1.27 million global deaths in 2019 and contributed to 4.95 million deaths.
  • The misuse and overuse of antimicrobials in humans, animals, and plants are the main drivers in the development of drug-resistant pathogens.
  • AMR affects countries in all regions and at all income levels. Its drivers and consequences are exacerbated by poverty and inequality, and low- and middle-income countries are most affected.
  • AMR puts many of the gains of modern medicine at risk. It makes

抗微生物耐药性

• 关键事实

  • 抗微生物耐药性（AMR）是全球公共卫生和发展面临的主要威胁之一。据估计，2019年细菌性AMR直接导致了127万人死亡，并间接导致495万人死亡。
  • 在人类、动物和植物中滥用和过度使用抗微生物药物是导致耐药病原体发展的主要原因。
  • AMR影响所有地区和所有收入水平的国家。其驱动因素和后果由于贫困和不平等而加剧，低收入和中等收入国家受到的影响最大。
  • AMR将许多现代医学的成就置于危险之中。它使得

Antimicrobial Resistance

• Key Facts

  • The world faces an antibiotics pipeline and access crisis. There is an inadequate research and development pipeline in the face of rising levels of resistance, and an urgent need for additional measures to ensure equitable access to new and existing vaccines, diagnostics, and medicines.
  • In addition to death and disability, AMR has significant economic costs. The World Bank estimates that AMR could result in US$ 1 trillion additional healthcare costs by 2050, and US$ 1 trillion to US$ 3.4 trillion gross domestic product (GDP) losses per year by 2030.
  • Priorities to address AMR in human health include preventing all infections, which may result in inappropriate use of antimicrobials; ensuring universal access to quality diagnosis and appropriate treatment of infections; and strategic information and innovation, for example, surveillance of AMR and antimicrobial consumption/use.

抗微生物耐药性

• 关键事实

  • 全球面临抗生素研发和可及性危机。在抗药性水平上升的情况下，研发管道不足，迫切需要采取额外措施确保新老疫苗、诊断工具和药物的公平获取。
  • 除了死亡和残疾，AMR还带来巨大的经济成本。世界银行估计，到2050年，AMR可能导致1万亿美元的额外医疗成本，到2030年，每年将导致1万亿美元至3.4万亿美元的国内生产总值（GDP）损失。
  • 解决AMR在人类健康中的优先事项包括预防所有可能导致不当使用抗微生物药物的感染；确保普遍获得优质诊断和适当治疗感染；以及战略性的信息和创新，例如AMR和抗微生物药物使用/消费的监测。

The global set of relationships between protein targets of all drugs and all disease-gene products in the human protein–protein interaction or 'interactome' network remains uncharacterized.
We built a bipartite graph composed of US Food and Drug Administration–approved drugs and proteins linked by drug–target binary associations. The resulting network connects most drugs into a highly interlinked giant component, with strong local clustering of drugs of similar types according to Anatomical Therapeutic Chemical classification. Topological analyses of this network quantitatively showed an overabundance of 'follow-on' drugs, that is, drugs that target already targeted proteins. By including drugs currently under investigation, we identified a trend toward more functionally diverse targets improving polypharmacology.

全球所有药物的蛋白靶标与人类蛋白质-蛋白质相互作用或“相互组学”网络中的所有疾病基因产物之间的关系仍未被充分表征。
我们构建了一个二分图，包含了美国食品药品监督管理局（FDA）批准的药物和通过药物-靶标二元关联连接的蛋白质。所得网络将大多数药物连接成一个高度相互连接的巨大组件，且根据解剖治疗化学分类，相似类型的药物有着强烈的局部聚类。该网络的拓扑分析定量地显示出“跟进”药物的过度集中，即靶向已经被靶向的蛋白质的药物。通过包括目前正在研究的药物，我们发现了一个趋势，即越来越多功能多样的靶标改善了多药理学。

The common analogy of drug action is that of a lock and key, with a drug acting as a selective 'key' that fits into the 'lock' of a specific drug target.
Over the past two decades, the concept of designing exquisitely selective ligands to avoid unwanted side effects has become the predominant paradigm in drug discovery. However, a growing body of post-genomic biology is revealing a far more complex picture of drug action. An elegant new study by Yıldırım et al. in this issue illustrates not only that there are many keys for each lock but also that it is far more common than expected for a single key to fit multiple locks.

药物作用的常见类比是锁与钥匙的关系，其中药物作为一个选择性的“钥匙”，适配特定药物靶标的“锁”。
在过去的二十年中，设计极为选择性的配体以避免不良副作用的概念已经成为药物发现中的主导范式。然而，越来越多的后基因组学生物学研究揭示了药物作用的远复杂于以往的图景。Yıldırım等人在本期中的一项精美新研究表明，不仅每个“锁”有许多“钥匙”，而且单一的“钥匙”适配多个“锁”的现象比预期的更为常见。

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.
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.

药物发现中的主导范式是设计具有最大选择性的配体作用于单一药物靶标的概念。
然而，许多有效的药物是通过调节多个蛋白质而非单一靶标发挥作用的。系统生物学的进展揭示了表型的稳健性和网络结构，强烈暗示，与多靶标药物相比，极具选择性的化合物可能表现出低于预期的临床疗效。
整合网络生物学和多药理学有望扩展当前可药靶标的机会空间。然而，多药理学的合理设计面临着巨大的挑战，亟需新的方法来验证靶标组合并优化多个结构-活性关系，同时保持药物样性质。
这些领域的进展正在为药物发现的下一个范式——网络药理学奠定基础。

第八章

软件课

第九章

软件课

第十章

SWISS-MODEL is a fully automated protein structure homology modeling server, accessible via the ExPASy web server, or from the program DeepView (Swiss Pdb-Viewer). The purpose of this server is to make protein modeling accessible to all life science researchers worldwide.

SWISS-MODEL 是一个全自动的蛋白质结构同源建模服务器，可以通过ExPASy网站服务器或程序DeepView（Swiss Pdb-Viewer）访问。该服务器的目的是使全球所有生命科学研究人员都能使用蛋白质建模。

第十一章

一、分子对接的基本理论

• Molecular Docking is a method which anticipates the favored orientation of ligand against receptor (Protein) to make a stable complex.
• The favored orientation can be used to predict the strength of connection or binding affinity between ligand and protein by utilizing scoring functions.
• Docking is often applied to predict the binding orientation of drug candidates against protein targets to forecast the affinity and activity of the drug.
• The main aim of molecular docking is to computationally simulate the molecular recognition process and achieve an optimized conformation so that the free energy of the overall system is minimized.

一、分子对接的基本理论

• 分子对接是一种预测配体与受体（蛋白质）之间偏好取向的方法，以形成稳定的复合物。
• 偏好取向可用于通过利用打分函数预测配体与蛋白质之间的连接强度或结合亲和力。
• 对接常用于预测药物候选分子与蛋白质靶标的结合取向，以预测药物的亲和力和活性。
• 分子对接的主要目标是计算模拟分子识别过程，并获得优化的构象，从而使整个系统的自由能最小化。

分子对接的分类

• (1) Lock and Key/Rigid Docking: Both the receptor and ligand are maintained fixed, and docking is executed.
• (2) Induced fit/Flexible Docking: In induced fit docking, both the ligand and the receptor are conformationally flexible. Every rotation, the surface cell occupancy and energy are calculated; later, the most optimum pose is selected.

分子对接的分类

• (1) 锁钥模型/刚性对接：受体和配体都保持固定，然后执行对接。
• (2) 诱导契合/柔性对接：在诱导契合对接中，配体和受体都是构象灵活的。每次旋转时，计算表面细胞占据率和能量；然后选择最优构象。

分子对接的基本步骤

Step I – Preparation of Protein:
The three-dimensional structure of the protein should be retrieved from the Protein Data Bank (PDB). Afterward, the retrieved structure should be pre-processed. This includes removing water molecules from the cavity, stabilizing the charges, filling in the missing residues, generating the side chains, etc., according to the available parameters.

Step II – Active Site Prediction:
After the preparation of the protein, the active site of the protein should be predicted. The receptor might possess many active sites, but only the one of interest should be selected. Typically, water molecules and hetero atoms, if present, are removed.

Step III – Preparation of Ligand:
Ligands can be retrieved from several databases such as ZINC, PubChem, or can be sketched using ChemSketch tool. When selecting the ligand, Lipinski's Rule of 5 can be applied.

Step IV – Docking:
The ligand is docked against the protein, and the interactions are analyzed. The scoring function gives a score based on the best-docked ligand complex, which is then selected.

分子对接的基本步骤

步骤 I – 蛋白质准备：
应从蛋白质数据银行（PDB）中检索蛋白质的三维结构；之后，检索到的结构需要预处理。这包括去除腔内的水分子、稳定电荷、填补缺失的残基、生成侧链等，具体操作根据可用的参数进行。

步骤 II – 活性位点预测：
蛋白质准备好后，应预测蛋白质的活性位点。受体可能具有多个活性位点，但只应选择一个关注的位点。通常，水分子和异源原子（如果存在）会被去除。

步骤 III – 配体准备：
配体可以从多个数据库（如ZINC、PubChem）中检索，或者使用ChemSketch工具进行绘制。在选择配体时，可以应用Lipinski的五条法则。

步骤 IV – 对接：
配体与蛋白质进行对接，并分析相互作用。打分函数根据最佳对接配体复合物给出评分，最终选择最佳构象。

Offline Molecular Docking (AutoDock, Discovery Studio)

What is AutoDock?
AutoDock is a suite of automated docking tools designed to predict how small molecules, such as substrates or drug candidates, bind to a receptor with a known 3D structure.

The current distributions of AutoDock consist of two generations of software:

  • AutoDock 4
  • AutoDock Vina

AutoDock 4 consists of two main programs:

  • AutoDock: Performs the docking of the ligand to a set of grids that describe the target protein.
  • AutoGrid: Pre-calculates these grids.

AutoDock Vina does not require the user to choose atom types and pre-calculate grid maps for them. Instead, it calculates the grids internally for the necessary atom types, and it does this virtually instantaneously.

Additionally, AutoDockTools (ADT) is a graphical user interface developed to help set up which bonds will be treated as rotatable in the ligand and to analyze the docking results.

离线分子对接（Autodock，Discovery Studio）

什么是AutoDock？
AutoDock是一套自动化对接工具，旨在预测小分子（如底物或药物候选分子）如何与已知三维结构的受体结合。

当前的AutoDock分发版本包括两个软件版本：

  • AutoDock 4
  • AutoDock Vina

AutoDock 4实际上由两个主要程序组成：

  • AutoDock：将配体与描述目标蛋白的网格进行对接。
  • AutoGrid：预先计算这些网格。

AutoDock Vina不需要选择原子类型并预先计算它们的网格图。相反，它内部计算所需原子类型的网格，并且几乎瞬间完成这一过程。

此外，还开发了一个名为AutoDockTools（简称ADT）的图形用户界面，除了其他功能外，它有助于设置哪些键将在配体中被视为可旋转的，并用于分析对接结果。

Case Sharing

Abstract:
M6A (N6-methyladenosine) plays a significant role in regulating RNA processing, splicing, nucleation, translation, and stability. AlkB homologue 5 (ALKBH5) is an Fe(II)/2-oxoglutarate (2-OG)-dependent dioxygenase that demethylates mono- or dimethylated adenosines. ALKBH5 can be regarded as an oncogenic factor for various human cancers. However, the discovery of potent and selective ALKBH5 inhibitors remains a challenge. We identified DDO-2728 as a novel and selective inhibitor of ALKBH5 by structure-based virtual screening and optimization. DDO-2728 was not a 2-oxoglutarate analogue and could selectively inhibit the demethylase activity of ALKBH5 over FTO (fat mass and obesity-associated protein, also known as ALKBH9). DDO-2728 increased the abundance of m6A modifications in AML cells, reduced the mRNA stability of TACC3, and inhibited cell cycle progression. Furthermore, DDO-2728 significantly suppressed tumor growth in the MV4−11 xenograft mouse model and showed a favorable safety profile. Collectively, our results highlight the development of a selective probe for ALKBH5 that will pave the way for the further study of ALKBH5 targeting therapies.

摘要： M6A（N6-甲基腺苷）在调节RNA加工、剪接、核聚合、翻译和稳定性方面起着重要作用。AlkB同源物5（ALKBH5）是一种Fe(II)/2-酮戊二酸（2-OG）依赖的二氧化物酶，能够去甲基化单甲基或双甲基腺苷。ALKBH5可以被视为多种人类癌症的致癌因子。然而，发现强效且具有选择性的ALKBH5抑制剂仍然是一个挑战。我们通过基于结构的虚拟筛选和优化，鉴定出DDO-2728作为ALKBH5的新型选择性抑制剂。DDO-2728并不是2-酮戊二酸的类似物，且能够选择性地抑制ALKBH5的去甲基化活性，而对FTO（脂肪质量和肥胖相关蛋白，也称为ALKBH9）几乎没有抑制作用。DDO-2728增加了AML细胞中m6A修饰的丰度，降低了TACC3的mRNA稳定性，并抑制了细胞周期进程。此外，DDO-2728显著抑制了MV4−11异种移植小鼠模型中的肿瘤生长，并显示出良好的安全性。总的来说，我们的结果突出了ALKBH5选择性探针的开发，这将为进一步研究ALKBH5靶向治疗铺平道路。

第十二章

Historical Definition:
The term "pharmacophore" was used to indicate the functional or structural capacity of a compound with specific characteristics towards a biological target.

Modern Understanding (IUPAC):
The pharmacophore is the ensemble of steric and electronic features that is necessary to ensure optimal supra-molecular interactions with a specific biological target structure and to trigger (or block) its biological response.

历史定义：
“药效基”一词用于表示化合物具备特定特征，能够对生物靶标产生功能性或结构性作用的能力。

现代理解（IUPAC）：
药效基是确保与特定生物靶标结构进行最佳超分子相互作用的必要空间和电子特征集合，从而触发（或阻断）其生物学反应。

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