Department of Chemistry, University of Silesia, 40007 Katowice, Poland.
Int J Mol Sci. 2021 May 14;22(10):5212. doi: 10.3390/ijms22105212.
A key question confronting computational chemists concerns the preferable ligand geometry that fits complementarily into the receptor pocket. Typically, the postulated 'bioactive' 3D ligand conformation is constructed as a 'sophisticated guess' (unnecessarily geometry-optimized) mirroring the pharmacophore hypothesis-sometimes based on an erroneous prerequisite. Hence, 4D-QSAR scheme and its 'dialects' have been practically implemented as higher level of model abstraction that allows the examination of the multiple molecular conformation, orientation and protonation representation, respectively. Nearly a quarter of a century has passed since the eminent work of Hopfinger appeared on the stage; therefore the natural question occurs whether 4D-QSAR approach is still appealing to the scientific community? With no intention to be comprehensive, a review of the current state of art in the field of receptor-independent (RI) and receptor-dependent (RD) 4D-QSAR methodology is provided with a brief examination of the 'mainstream' algorithms. In fact, a myriad of 4D-QSAR methods have been implemented and applied practically for a diverse range of molecules. It seems that, 4D-QSAR approach has been experiencing a promising renaissance of interests that might be fuelled by the rising power of the graphics processing unit (GPU) clusters applied to full-atom MD-based simulations of the protein-ligand complexes.
一个令计算化学家关注的关键问题是，哪种配体几何形状最适合互补地进入受体口袋。通常，假设的“生物活性”3D 配体构象被构建为“复杂的猜测”（不必要的几何优化），反映了药效团假说——有时基于错误的前提。因此，4D-QSAR 方案及其“方言”已经实际实现为更高层次的模型抽象，允许分别检查多个分子构象、取向和质子化表示。自霍普芬格的杰出工作问世以来，已经过去了将近四分之一个世纪；因此，自然而然地会出现这样一个问题：4D-QSAR 方法是否仍然吸引科学界的关注？本综述无意面面俱到，提供了受体独立（RI）和受体依赖（RD）4D-QSAR 方法领域的当前技术状态的回顾，并简要检查了“主流”算法。事实上，已经实现并实际应用了无数的 4D-QSAR 方法，用于各种分子。似乎，4D-QSAR 方法正在经历一场有前途的复兴，这可能得益于应用于基于 MD 的全原子蛋白-配体复合物模拟的图形处理单元（GPU）集群的兴起。
