The fast-growing body of experimental data on metalloenzymes and organometallic compounds is fostering the exploitation of metal–ligand interactions for the design of new drugs. Atomistic understanding of the metal–ligand interactions will help us identify potent metalloenzyme inhibitors and metallodrugs. Static docking calculations have proved effective in identifying hit compounds that target metalloproteins. However, the flexibility, dynamics and electronic structure of metal-centred complexes pose difficult challenges for shaping metal–ligand interactions in structure-based drug design. In this respect, once-prohibitive quantum mechanics-based strategies and extensive molecular simulations are rapidly becoming practical approaches for fast-paced drug discovery. These methods account for ligand exchange and structural flexibility at metal-centred complexes and provide good estimates of the thermodynamics and kinetics of metal-aided drug binding. This Perspective examines the successes, limitations and new avenues for modelling metalloenzyme inhibitors and metallodrugs to further explore and expand the unconventional chemical space of these distinctive drugs.

关于金属酶和有机金属化合物的实验数据迅速增长，正在促进金属-配体相互作用的开发，以用于新药的设计。对金属-配体相互作用的原子学理解将有助于我们确定有效的金属酶抑制剂和金属药物。事实证明，静态对接计算可有效识别靶向金属蛋白的命中化合物。但是，以金属为中心的配合物的灵活性，动力学和电子结构对在基于结构的药物设计中塑造金属-配体相互作用提出了艰巨的挑战。在这方面，基于禁忌量子力学的策略和广泛的分子模拟正迅速成为快节奏药物发现的实用方法。这些方法说明了以金属为中心的络合物的配体交换和结构柔性，并提供了金属辅助药物结合的热力学和动力学的良好估计。本《观点》探讨了建模金属酶抑制剂和金属药物的成功，局限性和新途径，以进一步探索和扩展这些独特药物的非常规化学空间。