Pharmacophore-Based Virtual Screening
Pharmacophore-Based Virtual Screening
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DOI：
10.1007/978-1-60761-839-3_11
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发表时间：
2011-01-01
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影响因子：
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通讯作者：
Horvath, Dragos
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作者：
Horvath, Dragos
本章回顾了药效团建模领域的最新发展，涵盖方法论和应用 基于药效团的虚拟筛选如今是一项成熟的技术，在药物化学实验室中得到了广泛接受。然而，与任何经验方法一样，它也有其特定的局限性，改进方法的努力仍在进行中药效团建模的优点和主要缺点 优点是简单性 - 非共价配体结合相互作用的复杂性质变得直观且易于被人脑理解 尽管计算机更适合药效团模式的比较，但化学家的直觉主要是支架导向的 其潜在的简化使得药效团模型无法提供配体结合倾向的完美预测 - 即使其所有现有的技术问题都得到解决。药效团建模和开发的每个步骤都有特定的缺点，从构象采样不足或不准确到药效团分型的模糊性（主要是由于化合物互变异构/质子化状态的不确定性），到复杂分子重叠计算中的计算机时间限制，以及当配体共晶体结构不可用时在活性位点中选择不适当的锚定点。药物化学中的筛选技术 - 特别是“支架跳跃”方法，可以发现具有所需生物活性的新化学类别载体
This chapter is a review of the most recent developments in the field of pharmacophore modeling, covering both methodology and application Pharmacophore-based virtual screening is nowadays a mature technology, very well accepted in the medicinal chemistry laboratory Nevertheless, like any empirical approach, it has specific limitations and efforts to improve the methodology are still ongoing Fundamentally, the core idea of "stripping" functional groups of their actual chemical nature in order to classify them into very few pharmacophore types, according to their dominant physico-chemical features, is both the main advantage and the main drawback of pharmacophore modeling The advantage is the one of simplicity - the complex nature of noncovalent ligand binding interactions is rendered Intuitive and comprehensible by the human mind Although computers are much better suited for comparisons of pharmacophore patterns, a chemist's intuition is primarily scaffold-oriented Its underlying simplifications render pharmacophore modeling unable to provide perfect predictions of ligand binding propensities - not even if all Its subsisting technical problems would be solved. Each step in pharmacophore modeling and exploitation has specific drawbacks from insufficient or inaccurate conformational sampling to ambiguities in pharmacophore typing (mainly due to uncertainty regarding the tautomeric/protonation status of compounds), to computer time limitations in complex molecular overlay calculations, and to the choice of inappropriate anchoring points in active sites when ligand cocrvstals structures are not available Yet, imperfections notwithstanding, the approach is accurate enough in order to be practically useful and actually is the most used virtual screening technique in medicinal chemistry - notably for "scaffold hopping" approaches, allowing the discovery of new chemical classes carriers of a desired biological activity