Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Pécs, Hungary.
Methods Mol Biol. 2020;2112:107-121. doi: 10.1007/978-1-0716-0270-6_8.
Exploration of binding sites of ligands (drug candidates) on macromolecular targets is a central question of molecular design. Although there are experimental and theoretical methods available for the determination of atomic resolution structure of drug-target complexes, they are often limited to identify only the primary binding mode (site and conformation). Systematic exploration of multiple (allosteric or prerequisite) binding modes is a challenge for present methods. The Wrapper module of our new method, Wrap 'n' Shake, answers this challenge by a fast, computational blind docking approach. Beyond the primary (orthosteric) binding mode, Wrapper systematically produces all possible binding modes of a drug scanning the entire surface of the target. In several fast blind docking cycles, the entire surface of the target molecule is systematically wrapped in a monolayer of N ligand copies. The resulted target-ligand complex structure can be used as it is, or important ligand binding modes can be further distinguished in molecular dynamics shakers. Wrapper has been tested on important protein targets of drug design projects on cellular signaling and cancer. Here, we provide a practical description of the application of Wrapper.
配体（药物候选物）与生物大分子靶标结合部位的探索是分子设计的核心问题。虽然已经有用于确定药物-靶标复合物原子分辨率结构的实验和理论方法，但它们通常仅限于识别主要的结合模式（部位和构象）。系统地探索多种（变构或先决）结合模式是目前方法的一个挑战。我们的新方法 Wrap 'n' Shake 的包装模块通过快速、计算盲对接方法来应对这一挑战。除了主要（正位）结合模式外，包装还通过扫描目标的整个表面，系统地生成药物的所有可能的结合模式。在几个快速的盲对接循环中，目标分子的整个表面被单层 N 个配体副本包裹。得到的靶标-配体复合物结构可以直接使用，或者可以在分子动力学摇床中进一步区分重要的配体结合模式。Wrapper 已经在细胞信号和癌症等药物设计项目的重要蛋白质靶标上进行了测试。在这里，我们提供了 Wrapper 应用的实用描述。
