Interindividual variability in drug response constitutes a major concern in pharmacotherapy. While polymorphisms in genes involved in drug disposition have been extensively studied, drug target variability remains underappreciated. By mapping the genomic variability of all human drug target genes onto high-resolution crystal structures of drug target complexes, we identified 1094 variants localized within 6 Å of drug-binding pockets and directly affecting their geometry, topology, or physicochemical properties. We experimentally show that binding site variants affect pharmacodynamics with marked drug- and variant-specific differences. In addition, we demonstrate that a common BCHE variant confers resistance to tacrine and rivastigmine, which can be overcome by the use of derivatives based on squaric acid scaffolds or tryptophan conjugation. These findings underscore the importance of genetic drug target variability and demonstrate that integration of genomic data and structural information can inform personalized drug selection and genetically guided drug development to overcome resistance.

中文翻译：

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人类药物靶基因的罕见遗传变异调节药物反应并可指导精准医疗

药物反应的个体差异是药物治疗中的一个主要问题。虽然已经广泛研究了涉及药物处置的基因中的多态性，但药物靶标变异性仍然未被充分认识。通过将所有人类药物靶基因的基因组变异性映射到药物靶复合物的高分辨率晶体结构上，我们确定了 1094 个位于药物结合口袋 6 Å 内并直接影响其几何形状、拓扑结构或物理化学性质的变体。我们通过实验表明，结合位点变体会影响药效学，并具有明显的药物和变体特异性差异。此外，我们证明了一个常见的BCHE变体赋予对他克林和卡巴拉汀的抗性，这可以通过使用基于方酸支架或色氨酸缀合的衍生物来克服。这些发现强调了基因药物靶点变异性的重要性，并证明基因组数据和结构信息的整合可以为个性化药物选择和基因指导药物开发提供信息以克服耐药性。