6XDT
Carbonmonoxy hemoglobin in complex with the antisickling agent methyl 5-((2-formyl-4-methoxyphenoxy)methyl)picolinate
Summary for 6XDT
| Entry DOI | 10.2210/pdb6xdt/pdb |
| Descriptor | Hemoglobin subunit alpha, Hemoglobin subunit beta, CARBON MONOXIDE, ... (6 entities in total) |
| Functional Keywords | hemoglobin, aromatic aldehyde, antisickling, allosteric effector, oxygen transport |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 65233.71 |
| Authors | Pagare, P.P.,Safo, M.K.,Musayev, F.N. (deposition date: 2020-06-11, release date: 2020-12-02, Last modification date: 2024-12-25) |
| Primary citation | 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 Cited by 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: 33205981DOI: 10.1021/acs.jmedchem.0c01287 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
Download full validation report
