7ZLD

Crystal Structure of Unlinked NS2B_NS3 Protease from Zika Virus in Complex with Inhibitor MI-2223

7ZLD の概要

• エントリーDOI: 10.2210/pdb7zld/pdb
• 分子名称: Serine protease subunit NS2B, Serine protease NS3, (2~{S})-2-[2-[3-(aminomethyl)phenyl]ethanoylamino]-6-azanyl-~{N}-[(2~{S})-6-azanyl-1-[[(5~{R})-6-azanyl-5-carbamimidamido-6-oxidanylidene-hexyl]amino]-1-oxidanylidene-hexan-2-yl]hexanamide, ... (4 entities in total)
• 機能のキーワード: flavivirin, serine protease, viral protein, ns2b-ns3, zika virus
• 由来する生物種: Zika virus; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 25493.74

構造登録者

Huber, S.,Steinmetzer, T. (登録日: 2022-04-14, 公開日: 2022-12-28, 最終更新日: 2024-02-07)

主引用文献

Hammerschmidt, S.J.,Huber, S.,Braun, N.J.,Lander, M.,Steinmetzer, T.,Kersten, C.
Thermodynamic characterization of a macrocyclic Zika virus NS2B/NS3 protease inhibitor and its acyclic analogs.
Arch Pharm, 356:e2200518-e2200518, 2023

PubMed Abstract: Cyclization of small molecules is a widely applied strategy in drug design for ligand optimization to improve affinity, as it eliminates the putative need for structural preorganization of the ligand before binding, or to improve pharmacokinetic properties. In this work, we provide a deeper insight into the binding thermodynamics of a macrocyclic Zika virus NS2B/NS3 protease inhibitor and its linear analogs. Characterization of the thermodynamic binding profiles by isothermal titration calorimetry experiments revealed an unfavorable entropy of the macrocycle compared to the open linear reference ligands. Molecular dynamic simulations and X-ray crystal structure analysis indicated only minor benefits from macrocyclization to fixate a favorable conformation, while linear ligands retained some flexibility even in the protein-bound complex structure, possibly explaining the initially surprising effect of a higher entropic penalty for the macrocyclic ligand.

PubMed: 36480352
DOI: 10.1002/ardp.202200518

実験手法

X-RAY DIFFRACTION (1.61 Å)