伦敦论文代写 生物学论文 Examining The Covalent Modifier In Drug Discovery
制药行业通常忽视或过滤筛选含有潜在活性的功能代表调节靶蛋白通过非共价相互作用的化合物打。事实上，潜在的多余的共价键相互作用，这些活性的候选药物如谷胱甘肽（GSH）生物试剂或有害生物的目标（目标蛋白质，DNA，等）可能结果不利的毒理学结果。[ 1 ]这些不良反应，可以观察到早期，以及延迟毒性，由于无论是免疫或组织学因素（表1）。[ 2 ]
Pharmaceutical industry usually disregard or filter out screening hits containing potentially reactive functionality behalf of compounds that modulate target proteins through noncovalent interactions. Indeed, the potential indiscriminant covalent interactions of these reactive drug candidates with biological nucleophiles like glutathione (GSH) or with unwanted biological target (off-target proteins, DNA, etc.) could results to unfavourable toxicological outcomes. [1] These adverse responses can be observed early as well as delayed toxicity due to either immunological or histological factors (Table 1). [2]
These may occur either acutely or as a delayed response In the case of immunological (allergic) response, either a drug-protein complex or a degradation product of such a complex can act as a stimulant for the immune system (Figure 1).
Figure 1. Postulated mechanism for drug hypersensitivity reactions.
This pathway can be achieved by either a reactive parent compound or a metabolite.
即使化合物在临床前模型中没有严重的毒理学结果，特异性反应可以表现在人类的临床试验或出现一旦实体被暴露到一个更大的病人池。不幸的是，预测危及生命的特殊不良事件在人类在临床前阶段一直回避。其结果是，往往是电阻朝向含有反应性功能的药物的开发，即使当反应性是温和的，仅限于生化指标。
另外，有控制的情况下，目标特定的共价修饰已被证明是有用的药物，药物或生物标志物的生物测定的发展。事实上，越来越多的药物发挥其药理作用的酶，受体或结构蛋白的共价修饰的目标。[ 3 ]所有这些化合物的分子结构，提出了一种化学反应片段“弹头”是能够建立共价键作用，可逆与否，与一个或多个蛋白质的表面或内部的蛋白质腔暴露的亲核残基。
Even when compounds present no grave toxicological outcome in preclinical models, idiosyncratic reactions can be manifested in human clinical trials or arise once the entity is exposed to a larger patient pool. Unfortunately, predicting life-threatening idiosyncratic adverse events in humans at the preclinical stage has been evasive. As a result, there is often resistance toward the development of drugs containing reactive functionality, even when the reactivity is modest and confined to the biochemical target.
Alternatively, there are instances where controlled, targets specific covalent modification has proven to be useful to the development of drugs, pharmacological tools or biomarkers for biological assay. Indeed, an increasing numbers of drugs exert their pharmacological functions on enzymes, receptors or structural protein by covalent modification of target. [3] All of these compounds presents a molecular structure in which a chemically reactive fragment "warhead" is able to establish covalent interactions, reversible or not, with one or more nucleophilic residues exposed on protein's surface or into an inner protein cavity.
作为一种药物，共价结合，其中所需的生物目标通常是，但不完全和不可逆失活，提供长期目标在低的微摩尔或纳摩尔范围。他们的目标选择性取决于他们的结构，以及他们的战斗部的反应性。而前者的药物目标识别和适当的弹头的定位是很重要的，后者是确保有效的共价结合到目标不偏离目标nuclephyles反应基本。最好的药理作用，具有很高的选择性和生物利用度，是通过共价修饰是典型的不良反应与亲核试剂溶液在生理条件下，但在适当的定位将选择性地与靶蛋白在亲核试剂的反应。[ 4 ]
化合物能够选择性地结合的半胱氨酸残基的硫醇部分蛋白质不与其他亲核试剂反应，吸引了全世界的科学界的兴趣。事实上，如果与其他亲核试剂反应的化合物相比（如丝氨酸和酪氨酸活性分子），这类化合物的活性半胱氨酸型可以提供一个额外的选择，超出了拟合优化结构提供适当的调制。这是因为在一个主要的蛋白质结构的半胱氨酸残基通常比其他结构的氨基酸的数目少。这样，在折叠的蛋白质结构的半胱氨酸残基的位置可作为特异结合点共价修饰半胱氨酸捕获能力，用适当的结构优化，对所有其他不需要暴露蛋白半胱氨酸。
As a drug, the covalent binding of one of these compounds to the desired biological target usually, but not exclusively, provides prolonged and irreversible target inactivation at low micromolar or nanomolar range. Their target selectivity depend by their structure as well as by their warhead reactivity. While the former is important for drug-target recognition and for proper warhead positioning, the latter is fundamental to ensure an effective covalent binding to the target without react with off-target nuclephyles. The best pharmacological profile, with high selectivity and bioavailability, is achieved when the covalent modifier is typically poorly reactive with solution nucleophiles under physiological conditions but yet upon appropriate positioning will selectively react with a nucleophile within the target protein. [4]
Compounds able to selectively bind the thiol portion of cysteine residues on proteins without react with other nucleophiles are attracting the interest of scientific community around the world. Indeed, if compared with other nucleophiles-reactive compounds (such as serine or tyrosine-reactive molecules), the cysteine oriented reactivity of these kind of compounds could furnish an additional source of selectivity that is beyond of fitting optimization provided by proper structural modulation. This is because of cysteine residues in a primary protein structure are usually few than the number of other structural amino acids. In this way, the positions of cysteines on folded protein structure can be used as specific binding point for cysteine trapping covalent modifiers able, with a proper structural optimization, to discriminate all other undesired cysteine exposing proteins.
伦敦论文代写 生物学论文 Examining The Covalent Modifier In Drug Discovery
