Abstract

The chemical structure of PF-07321332, the first orally available Covid-19 clinical candidate, has recently been revealed by Pfizer. No information has been provided about the interaction pattern between PF-07321332 and its biomolecular counterpart, the SARS-CoV-2 main protease (M^pro). In the present work, we exploited Supervised Molecular Dynamics (SuMD) simulations to elucidate the key features that characterise the interaction between this drug candidate and the protease, emphasising similarities and differences with other structurally related inhibitors such as Boceprevir and PF-07304814. The structural insights provided by SuMD will hopefully be able to inspire the rational discovery of other potent and selective protease inhibitors.

摘要

辉瑞公司最近披露了首个口服 Covid-19临床候选药物 PF-07321332 的化学结构。尚未提供有关 PF-07321332 与其生物分子对应物 SARS-CoV-2 主要蛋白酶 (M ^pro )之间相互作用模式的信息。在目前的工作中，我们利用监督分子动力学 (SuMD) 模拟来阐明表征该候选药物与蛋白酶之间相互作用的关键特征，强调与其他结构相关抑制剂如 Boceprevir 和 PF-07304814 的异同。SuMD 提供的结构见解有望激发对其他有效和选择性蛋白酶抑制剂的合理发现。