6XDT

Carbonmonoxy hemoglobin in complex with the antisickling agent methyl 5-((2-formyl-4-methoxyphenoxy)methyl)picolinate

6XDT の概要

• エントリーDOI: 10.2210/pdb6xdt/pdb
• 分子名称: Hemoglobin subunit alpha, Hemoglobin subunit beta, CARBON MONOXIDE, ... (6 entities in total)
• 機能のキーワード: hemoglobin, aromatic aldehyde, antisickling, allosteric effector, oxygen transport
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 65233.71

構造登録者

Pagare, P.P.,Safo, M.K.,Musayev, F.N. (登録日: 2020-06-11, 公開日: 2020-12-02, 最終更新日: 2024-12-25)

主引用文献

Pagare, P.P.,Ghatge, M.S.,Chen, Q.,Musayev, F.N.,Venitz, J.,Abdulmalik, O.,Zhang, Y.,Safo, M.K.
Exploration of Structure-Activity Relationship of Aromatic Aldehydes Bearing Pyridinylmethoxy-Methyl Esters as Novel Antisickling Agents.
J.Med.Chem., 63:14724-14739, 2020

PubMed Abstract: Aromatic aldehydes elicit their antisickling effects primarily by increasing the affinity of hemoglobin (Hb) for oxygen (O). However, challenges related to weak potency and poor pharmacokinetic properties have hampered their development to treat sickle cell disease (SCD). Herein, we report our efforts to enhance the pharmacological profile of our previously reported compounds. These compounds showed enhanced effects on Hb modification, Hb-O affinity, and sickling inhibition, with sustained pharmacological effects . Importantly, some compounds exhibited unusually high antisickling activity despite moderate effects on the Hb-O affinity, which we attribute to an O-independent antisickling activity, in addition to the O-dependent activity. Structural studies are consistent with our hypothesis, which revealed the compounds interacting strongly with the polymer-stabilizing αF-helix could potentially weaken the polymer. studies with wild-type mice demonstrated significant pharmacologic effects. Our structure-based efforts have identified promising leads to be developed as novel therapeutic agents for SCD.

PubMed: 33205981
DOI: 10.1021/acs.jmedchem.0c01287

実験手法

X-RAY DIFFRACTION (1.9 Å)