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伦敦论文代写 生物学论文 Examining The Covalent Modifier In Drug Discovery

伦敦论文代写 生物学论文 Examining The Covalent Modifier In Drug Discovery

这个概念已经被应用于药物如半胱氨酸蛋白酶抑制剂的发展(组织蛋白酶和caspase抑制剂),酪氨酸激酶抑制剂(EGFR抑制剂)和脂肪酶抑制剂(MGL半胱氨酸捕兽抑制剂)也对药理学工具的发展定位、目标和验证研究。

1.1.1共价药物靶相互作用:药理工具或药物设计正交的方法。

本文所提出的例子提供了强有力的证据,共价修饰可以是安全和有效的治疗方法。虽然在许多情况下,抑制的机制被确定后疗效实现,一个可以采用一个共价修饰的方法从一个程序的开始。

This concept has been applied to the development of drugs such as cysteine-protease inhibitors (cathepsin and caspase inhibitors), tyrosine kinase inhibitors (EGFR inhibitors) and lipase inhibitors (MGL cysteine trappers inhibitors) but also to the development of pharmacological tools to localize, study and validate targets.

1.1.1 Covalent drug-target interaction: an orthogonal approach to design pharmacological tools or drugs.

The examples presented herein provide strong evidence that covalent modifiers can be safe and effective therapeutics. While in many instances the mechanism of inhibition was determined after efficacy was realized, one could adopt a covalent modifier approach from the beginning of a program.

这种方法的一个关键的成功因素是适当的选择战斗部部分。虽然有含有非常活跃的功能化合物的例子,如阿司匹林(活性酯)和磷霉素1(环氧),大多数成功的药物含有的活性衰减功能实现有针对性的调制。例如,卡巴拉汀1D乙酰胆碱酯酶结合激活氨基甲酸酯对裂解的催化三联活性位点丝氨酸。另一个例子是非那雄胺1U的优雅,作为一种选择性氢化受体从NADPH只有当绑定到5r-reductase.65此外,猫K抑制剂odanacatib 1x强调活性部位巯基腈的亲核加成。这些例子说明了如何在一个结构域内的战斗部的位置可以提供所需的治疗效果和安全性。

此外,前体药物的方法同样有效但更具挑战性。有一些药物,利用一个带着面具的核弹头电组件如H+/K+-ATP酶抑制剂(奥美拉唑1N例证),其中活性物种在药物行使其抑酸作用,胃的酸性环境中产生。这一目标的局部反应中间体的降低全身暴露和非目标toxicities.66畅销药氯吡格雷1转化为活性代谢产物,推测与P2Y12反应优先防止斯托克电位的形成。

这些成功的药物被发现无心插柳,或通过设计,我们可以利用现有的机械和/或结构信息,使未来的从头设计选择性共价修饰的洞察力。最重要的成功是蛋白质-配体相互作用的详细的结构信息的可用性,如来自X-射线晶体,以方便的复合设计和战斗部放置的细化。这种方法是通过EGFR抑制剂1T优雅的阐释,在适当位置放置米迦勒受体的反应很容易与亲核氨基酸侧链时,通过从内部基本胺援助。

One key success factor for this approach is the proper selection of the warhead moiety. Although there are examples of compounds containing very active functionality, such as aspirin (activated ester) and fosfomycin 1i (epoxide), a majority of the successful drugs contain functionality whose reactivity is attenuated to achieve targeted modulation. For example, the binding of rivastigmine 1d to acetylcholinesterase activates the carbamate toward cleavage by the active site serine of the catalytic triad. Another elegant example is finasteride 1u, which acts as a selective hydride acceptor from NADPH only when bound to 5R-reductase.65 In addition, the Cat K inhibitor odanacatib 1x highlights the reversible nucleophilic addition of an active site thiol to a nitrile. These examples illustrate how the location of the warhead within a structural motif can deliver both the desired therapeutic effect and safety profile.

Additionally, the prodrug approach is also valid but arguably more challenging. There are several drugs that utilize a masked warhead as the electrophilic component such as the H+/K+ ATPase inhibitors (exemplified by omeprazole 1n), where the reactive species is generated in the acidic environment of the stomach where the drug exercises its antisecretory effect. This target-localized formation of the reactive intermediate reduces systemic exposure and potential for off-target toxicities.66 The blockbuster drug clopidogrel 1o is converted to an active metabolite that is hypothesized to react preferentially with P2Y12 to prevent stoke.

Whether these successful drugs were discovered serendipitously or by design, we can use the insight provided by the available mechanistic and/or structural information to enable future de novo design of selective covalent modifiers. Paramount for success is the availability of detailed structural information on protein-ligand interaction, such as that derived from of X-ray crystallography, to facilitate the refinement of compound design and warhead placement. This approach is elegantly illustrated by the EGFR inhibitor 1t, where an appropriately placed Michael acceptor reacts readily with a nucleophilic amino acid side chain when facilitated by assistance from an internal basic amine moiety.

A systematic review of the known covalently modulated targets reveals several trends (Table 3, Charts 1 and 2). It is no surprise that the most prevalent covalently modified targets identified are enzymes (Chart 1). As a subset of the overall targets, the cysteine and serine residues are primarily modified, with few examples of other nucleophilic amino acid residues (Chart 2). Among the enzymes, proteases or hydrolases appear frequently. In addition, cofactor mediated enzymes are also represented. These data indicate that cofactor mediated enzymes or enzymes bearing an active site cysteine or serine represent attractive targets for covalent modification. The strategy to drug a target through employing covalent modifying approach could provide advantages under certain scenarios. There is typically a cost to improving the potency of lead structures that bind through noncovalent interactions. This endeavor must balance increases in molecule weight, lipophilicity, and hydrogen bonding functionality that can be detrimental to other important properties such as pharmacokinetics and ancillary pharmacology. In contrast, when a significant amount of binding energy is derived from the drug-protein covalent bond, there should be a reduction in the number noncovalent interactions needed to achieve desired potency. In the case of irreversible binders, drug concentrations in systemic circulation need only be available for a long enough period to achieve target coverage, potentially deemphasizing the need for a high, prolonged systemic drug load and therefore potentially mitigating off-target activity.67 Also, the half-life of the compound need not be long in order to achieve once a day or twice a day dosing. Certainly, reversible noncovalent inhibitors that display slow off-rates would also provide a similar benefit. While there will always be a healthy debate about pursuing molecules that bind covalently, this risk may be minimized by pursuing covalent modifiers that would be administered acutely or to patients with a life threatening disease.

已知的共价调节的目标的系统的审查揭示了几个趋势(表3,图表1和2)。最常见的共价修饰的靶点是酶(图1),这并不奇怪。作为整体目标的一个子集,半胱氨酸和丝氨酸残基主要是改性、与其他亲核氨基酸残基的几个例子(图2)。在酶、蛋白酶、水解酶的频繁出现。此外,辅因子介导的酶也表示。这些数据表明,辅因子介导的酶或酶的活性位点的半胱氨酸或丝氨酸代表共价修饰的有吸引力的目标。通过采用共价修饰的方法的策略,药物的目标,在一定的情况下,可以提供优势。这是一个典型的成本提高导致结合的结构,通过非共价键相互作用的效力。这种努力必须平衡的分子量,增加亲脂性,与氢结合的功能,可以对其他重要特性如和辅助药理药动学。相反,当结合大量能源是来自药物蛋白的共价键,应该有数量的非共价相互作用需要达到预期的效力减少。在不可逆的粘合剂的情况下,循环中的药物浓度,只需要提供一个足够长的时间来实现目标的覆盖,潜在地淡化为一个高的需要,延长系统的药物负荷,因此可能减轻了目标activity.67也,该化合物的半衰期不需要长时间以达到一天一次或一天两次的剂量。当然,可逆的非共价抑制剂,显示慢了速度也将提供类似的好处。虽然将永远是一个健康的辩论,追求分子共价结合,这种风险可能会被最小化,通过追求共价修饰,将给予急性或危及生命的疾病的患者。

Analysis of the pharmacodynamic needs of a particular therapy may lead one to consider irreversible covalent inhibition. For many diseases pharmacodynamic activity is correlated to the degree of target inhibition or occupancy. For therapies that require a high target occupancy for effective treatment, such as cancer or antibacterial therapeutics (where in the absence of high target coverage mutations may occur),68 irreversible covalent modulation could be the most effective means of treatment.

Conversely, there are therapeutic axes that would not benefit from complete covalent inhibition, wherein the complete shutdown of a primary pathway would lead to on-target toxicities. In these instances, irreversible covalent inhibition may not be appropriate. For example, in the case of warfarin, it is known that using the drug for an extended period of time (or at a high dose) can cause fatal bleeding. For this reason, warfarin is recommended for short-term use; when warfarin is used for long-term thrombosis therapy, patients are closely monitored.

That said, the industry is still searching for a safe and effective alternative to warfarin. Whether medicinal chemists pursue covalent or noncovalent modifiers, compounds should be selective for the desired target. This selectivity encompasses related pharmacological targets, as well as other endogenous nucleophilic moieties such as proteins, peptides (such as glutathione), and DNA. In any drug discovery program ancillary pharmacology studies are conducted to assess the potential liability for observing off-target toxicities in addition to in vitro safety studies. While selectivity criteria are identical for programs striving to develop either a covalent or noncovalent modifier, one might consider conducting studies to determine promiscuous binding earlier in a program utilizing a potentially reactive functional group.

It is interesting to consider how an organization might become better positioned to exploit covalent modification as a more general approach to drug discovery. For instance, one may consider building a focused screening set that would be populated with low molecular weight compounds that possess “low to moderately” reactive functionality. A lead identified from this collection could be optimized with information from crystallography and modeling studies. Medicinal chemists could further “fine-tune” reactivity, if needed, so covalent adduction is confined to the target protein. Of course opinions regarding an acceptable level of reactivity for a lead structure will always be defined differently throughout the industry. In addition, identification of functional groups beyond those mentioned in this review that selectively form covalent adducts could further enable this strategy.

伦敦论文代写 生物学论文 Examining The Covalent Modifier In Drug Discovery