Balazs Amber Y S, Davies Nichola L, Longmire David, Packer Martin J, Chiarparin Elisabetta
Chemistry, Oncology R&D, AstraZeneca, Waltham, Massachusetts 02451, United States.
Chemistry, Oncology R&D, AstraZeneca, Cambridge CB4 0QA, United Kingdom.
Magn Reson (Gott). 2021 Jun 23;2(1):489-498. doi: 10.5194/mr-2-489-2021. eCollection 2021.
Knowledge of free ligand conformational preferences (energy minima) and conformational dynamics (rotational energy barriers) of small molecules in solution can guide drug design hypotheses and help rank ideas to bias syntheses towards more active compounds. Visualization of conformational exchange dynamics around torsion angles, by replica exchange with solute tempering molecular dynamics (REST-MD), gives results in agreement with high-resolution H nuclear magnetic resonance (NMR) spectra and complements free ligand conformational analyses. Rotational energy barriers around individual bonds are comparable between calculated and experimental values, making the in-silico method relevant to ranking prospective design ideas in drug discovery programs, particularly across a series of analogs. Prioritizing design ideas, based on calculations and analysis of measurements across a series, efficiently guides rational discovery towards the "right molecules" for effective medicines.
了解溶液中小分子的游离配体构象偏好（能量最小值）和构象动力学（旋转能垒）可以指导药物设计假设，并有助于对想法进行排序，使合成偏向于更具活性的化合物。通过溶质回火分子动力学的副本交换（REST-MD）对扭转角周围的构象交换动力学进行可视化，得到的结果与高分辨率氢核磁共振（NMR）光谱一致，并补充了游离配体构象分析。各个键周围的旋转能垒在计算值和实验值之间具有可比性，使得这种计算机模拟方法与药物发现计划中前瞻性设计想法的排序相关，特别是对于一系列类似物。基于对一系列测量的计算和分析来确定设计想法的优先级，有效地指导合理发现，以找到有效药物的“正确分子”。
