Nitrogen-inversion rates and diffusion coefficients were measured using ¹H NMR for 14 drug-like molecules. The slow nitrogen-inversion rates interconverting the enantiomers of these molecules lay within a postulated intermediate range in terms of their ability to bind to proteins bounded by diffusion constraints, potentially affecting the availability, hence efficacy, of these compounds if they were utilized as drugs. The postulated intermediate range is based on a capture-volume concept, whereby the nitrogen inversion during the time a ligand takes to pass through a volume surrounding the protein binding site, as calculated by the diffusion rate, determines if it will influence ligand binding to the protein. In the systems examined here, the measured nitrogen-inversion rates and the times required to traverse the capture volume differed by a few orders of magnitude. Potentially more consequential are intermediate nitrogen-inversion rates in epimeric cases—since the energies of the interconverting species are unequal, a heavy bias against the eutomer might occur. The implications of an intermediate nitrogen-inversion rate are significant for in silico drug design, drug efficacy, molecular modeling of drug–protein binding, pharmacokinetics, drug enantiomer evaluation, etc. Due consideration of the process should thus be taken into account for drug development directions and in vitro evaluation.

中文翻译：

---

氮转化的中速会影响药效吗？

氮转化率和扩散系数使用¹14 种药物样分子的 H NMR。就这些分子与受扩散约束限制的蛋白质结合的能力而言，使这些分子的对映异构体相互转化的缓慢氮转化率处于假定的中间范围内，如果这些化合物用作药物，可能会影响这些化合物的可用性，从而影响其功效。假定的中间范围基于捕获体积概念，即在配体通过蛋白质结合位点周围体积期间的氮转化（由扩散速率计算）决定了它是否会影响配体与蛋白质结合位点的结合。蛋白质。在此处检查的系统中，测得的氮转化率和穿越捕获体积所需的时间相差几个数量级。可能更重要的是差向异构情况下的中间氮转化率——因为相互转化的物质的能量不相等，可能会发生对 eutomer 的严重偏见。中间氮转化率的影响对于计算机药物设计、药物功效、药物-蛋白质结合的分子建模、药代动力学、药物对映体评估等具有重要意义。 因此，应在药物开发中适当考虑该过程方向和体外评价。