Computational Drug Design and Biomedical Informatics Laboratory, Translational Medicine Research Institute (IIMT), CONICET-Universidad Austral, Derqui-Pilar, Buenos Aires, Argentina.
Austral Institute for Applied Artificial Intelligence, Universidad Austral, Derqui-Pilar, Buenos Aires, Argentina.
Methods Mol Biol. 2020;2114:257-268. doi: 10.1007/978-1-0716-0282-9_16.
The routine use of in silico tools is already established in drug lead design. Besides the use of molecular docking methods to screen large chemical libraries and thus prioritize compounds for purchase or synthesis, more accurate calculations of protein-ligand binding free energy has shown the potential to guide lead optimization, thus saving time and resources. Theoretical developments and advances in computing power have allowed quantum mechanical-based methods applied to calculations on biomacromolecules to be increasingly explored and used, with the purpose of providing a more accurate description of protein-ligand interactions and an enhanced level of accuracy in the calculation of binding affinities. It should be noted that the quantum mechanical formulation includes, in principle, all contributions to the energy, considering terms usually neglected in molecular mechanics force fields, such as electronic polarization, metal coordination, and covalent binding; moreover, quantum mechanical approaches are systematically improvable. By treating all elements and interactions on equal footing, and avoiding the need of system-dependent parameterizations, they provide a greater degree of transferability. In this review, we illustrate the increasing relevance of quantum mechanical methods for binding free energy calculation in the context of structure-based drug lead optimization, showing representative applications of the different approaches available.
计算机辅助药物设计中已常规使用计算机模拟工具。除了使用分子对接方法筛选大型化学库并优先选择购买或合成的化合物外，更精确地计算蛋白质-配体结合自由能显示出指导先导化合物优化的潜力，从而节省时间和资源。理论发展和计算能力的进步使得基于量子力学的方法可越来越多地应用于生物大分子的计算，目的是提供更准确的蛋白质-配体相互作用描述和更高水平的结合亲和力计算准确性。需要指出的是，量子力学公式化原则上包括对能量的所有贡献，考虑到通常在分子力学力场中忽略的术语，如电子极化、金属配位和共价键；此外，量子力学方法可以系统地改进。通过平等对待所有元素和相互作用，并且避免需要依赖于系统的参数化，它们提供了更大程度的可转移性。在本文综述中，我们说明了量子力学方法在基于结构的药物先导优化中计算结合自由能的相关性不断增加，并展示了不同方法的代表性应用。
