Pant Suyash, Jena Nihar R
Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Kolkata, India.
Discipline of Natural Sciences, Indian Institute of Information Technology, Design and Manufacturing, Jabalpur, India.
Front Med (Lausanne). 2022 Jul 6;9:921060. doi: 10.3389/fmed.2022.921060. eCollection 2022.
The Zika virus (ZIKV) protease is an attractive drug target for the design of novel inhibitors to control the ZIKV infection. As the protease substrate-binding site contains acidic residues, inhibitors with basic residues can be beneficial for the inhibition of protease activities. Molecular dynamics (MD) simulation and molecular mechanics with generalized Born and surface area solvation (MM/GBSA) techniques are employed herein to design potent peptide inhibitors and to understand the nature of the basic residues that can potentially stabilize the acidic residues of the protease substrate-binding site. It is found that the inclusion of K, R, and K at P1, P2, and P3 positions, respectively, and Y at the P4 position (YKRK) would generate a highly stable tetrapeptide-protease complex with a ΔG of ~ -80 kcal/mol. We have also shown that the C-terminal extension of this and the second most stable tetrapeptide (YRRR) with small polar residues, such as S and T would generate even more stable hexapeptide-protease complexes. The modes of interactions of these inhibitors are discussed in detail, which are in agreement with earlier experimental studies. Thus, this study is expected to aid in the design of novel antiviral drugs against the ZIKV.
寨卡病毒（ZIKV）蛋白酶是设计新型抑制剂以控制ZIKV感染的一个有吸引力的药物靶点。由于蛋白酶底物结合位点含有酸性残基，带有碱性残基的抑制剂可能有利于抑制蛋白酶活性。本文采用分子动力学（MD）模拟以及结合广义玻恩模型和表面积溶剂化的分子力学（MM/GBSA）技术来设计有效的肽类抑制剂，并了解可能稳定蛋白酶底物结合位点酸性残基的碱性残基的性质。研究发现，分别在P1、P2和P3位置引入K、R和K，以及在P4位置引入Y（YKRK）会产生一个高度稳定的四肽 - 蛋白酶复合物，其ΔG约为 -80 kcal/mol。我们还表明，用小的极性残基（如S和T）对该四肽以及第二稳定的四肽（YRRR）进行C端延伸会产生更稳定的六肽 - 蛋白酶复合物。详细讨论了这些抑制剂的相互作用模式，这与早期的实验研究一致。因此，预计本研究将有助于设计针对ZIKV的新型抗病毒药物。
