2022薛定谔秋季中文生命科学网络讲座 | 基于物理理论的计算模拟 – 如何准确预测小分子晶体的结构和溶解度

Speakers

Lingle Wang
Vice President

Abstract

对固态科学家来说，药物晶体形式的改变是药物研发后期甚至上市后是非常严重的，打击性极强的问题。这类新型的晶体形式可能表现出不同的，有可能是负面的特性。许多药物的多晶型消失，包括利托那韦、罗替戈汀和盐酸雷尼替丁等，给制药公司带来了巨大的损失并引发一系列患者诉讼。本次研讨会，我将介绍一种通过大规模回顾性验证和被实际药物制剂过程中的前瞻性研究所证明的、可靠且准确的方法来预测候选药物的所有低能量稳定多晶型物及其相对稳定性。此外，我们还将重点介绍通过自由能扰动 (FEP+) 方法准确计算晶体结构的热力学溶解度。

Emergence of unexpected crystal forms during late stages of drug development or after the initial launch of the drug is a very frustrating and serious problem for solid-state scientists. Since the newly emerged forms can exhibit different and potentially undesired properties, disappearing polymorphs for many drugs, including ritonavir, rotigotine and ranitidine hydrochloride for example, have caused big losses for pharmaceutical companies and series patient litigations. In this presentation, I will present a reliable and accurate method to predict all the low energy stable polymorphs of a given drug candidate and their relative stabilities, as demonstrated both from large scale retrospective validation and prospective studies in real drug formulation processes. I will also highlight the accurate calculations of the thermodynamic solubilities of crystal structures from free energy perturbation (FEP+) method.