Characterization of the non-covalent interaction between the PF-07321332 inhibitor and the SARS-CoV-2 main protease.
Characterization of the non-covalent interaction between the PF-07321332 inhibitor and the SARS-CoV-2 main protease.
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DOI：
10.1016/j.jmgm.2021.108042
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发表时间：
2022-01
影响因子：
2.9
通讯作者：
Procacci P
中科院分区：
文献类型：
--
作者：
Macchiagodena M;Pagliai M;Procacci P
我们使用基于使用显式溶剂的广泛分子动力学模拟的计算方法，在原子水平上研究了 PF-07321332 和 SARS-CoV-2 主要蛋白酶之间的非共价相互作用。 PF-07321332 的化学结构最近已被披露，是一种有前途的口服抗病毒临床候选药物，具有良好的体外抗 SARS-CoV-2 活性。该药物目前正与利托那韦联合进行 III 期临床试验，依赖于腈弹头对蛋白酶催化半胱氨酸的亲电攻击。使用两种不同的力场和主要蛋白酶催化二元体 HIS41-CYS145 的两种可能的质子化状态，对抑制剂与结合袋残基以及蛋白质表面上的水分子之间的非键相互作用进行了表征。当催化二元体处于中性状态时，非共价结合可能更强。分子动力学模拟似乎支持分两个步骤的抑制机制：首先与中性形式的二元体进行非共价加成，然后形成硫醇盐-咪唑鎓离子对和配体重新定位以最终完成亲电子攻击。
We have studied the non-covalent interaction between PF-07321332 and SARS-CoV-2 main protease at the atomic level using a computational approach based on extensive molecular dynamics simulations with explicit solvent. PF-07321332, whose chemical structure has been recently disclosed, is a promising oral antiviral clinical candidate with well-established anti-SARS-CoV-2 activity in vitro. The drug, currently in phase III clinical trials in combination with ritonavir, relies on the electrophilic attack of a nitrile warhead to the catalytic cysteine of the protease. Nonbonded interaction between the inhibitor and the residues of the binding pocket, as well as with water molecules on the protein surface, have been characterized using two different force fields and the two possible protonation states of the main protease catalytic dyad HIS41-CYS145. When the catalytic dyad is in the neutral state, the non-covalent binding is likely to be stronger. Molecular dynamics simulations seems to lend support for an inhibitory mechanism in two steps: a first non-covalent addition with the dyad in neutral form and then the formation of the thiolate-imidazolium ion pair and the ligand relocation for finalising the electrophilic attack.
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影响因子：
14.9
作者：
Dodda LS;Cabeza de Vaca I;Tirado-Rives J;Jorgensen WL
通讯作者：
Jorgensen WL
DOI：
10.1074/jbc.ac120.016154
发表时间：
2020-12-11
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Kneller DW;Phillips G;Weiss KL;Pant S;Zhang Q;O'Neill HM;Coates L;Kovalevsky A
通讯作者：
Kovalevsky A
影响因子：
7.7
作者：
Bhardwaj VK;Singh R;Das P;Purohit R
通讯作者：
Purohit R
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML
影响因子：
2.9
作者：
Huang, CK;Wei, P;Lai, LH
通讯作者：
Lai, LH