6BNR

Carbonmonoxy hemoglobin in complex with the antisickling agent 5-methoxy-2-(pyridin-2-ylmethoxy)benzaldehyde (INN310)

Summary for 6BNR

• Entry DOI: 10.2210/pdb6bnr/pdb
• Descriptor: Hemoglobin subunit alpha, Hemoglobin subunit beta, CARBON MONOXIDE, ... (6 entities in total)
• Functional Keywords: hemoglobin, aromatic aldehyde, antisickling, allosteric effector, alpha-cleft, oxygen transport
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 65117.64

Authors

Pagare, P.P.,Musayev, F.N.,Safo, M.K. (deposition date: 2017-11-17, release date: 2018-09-05, Last modification date: 2024-10-23)

Primary citation

Pagare, P.P.,Ghatge, M.S.,Musayev, F.N.,Deshpande, T.M.,Chen, Q.,Braxton, C.,Kim, S.,Venitz, J.,Zhang, Y.,Abdulmalik, O.,Safo, M.K.
Rational design of pyridyl derivatives of vanillin for the treatment of sickle cell disease.
Bioorg. Med. Chem., 26:2530-2538, 2018

PubMed Abstract: Hypoxia-induced polymerization of sickle hemoglobin (Hb S) is the principal phenomenon that underlays the pathophysiology and morbidity associated with sickle cell disease (SCD). Opportunely, as an allosteric protein, hemoglobin (Hb) serves as a convenient and potentially critical druggable target. Consequently, molecules that prevent Hb S polymerization (Hb modifiers), and the associated erythrocyte sickling have been investigated-and retain significant interest-as a viable therapeutic strategy for SCD. This group of molecules, including aromatic aldehydes, form high oxygen affinity Schiff-base adducts with Hb S, which are resistant to polymerization. Here, we report the design and synthesis of novel potent antisickling agents (SAJ-009, SAJ-310 and SAJ-270) based on the pharmacophore of vanillin and INN-312, a previously reported pyridyl derivative of vanillin. These novel derivatives exhibited superior in vitro binding and pharmacokinetic properties compared to vanillin, which translated into significantly enhanced allosteric and antisickling properties. Crystal structure studies of liganded Hb in the R2 quaternary state in complex with SAJ-310 provided important insights into the allosteric and antisickling properties of this group of compounds. While these derivatives generally show similar in vitro biological potency, significant structure-dependent differences in their biochemical profiles would help predict the most promising candidates for successful in vivo pre-clinical translational studies and inform further structural modifications to improve on their pharmacologic properties.

PubMed: 29655608
DOI: 10.1016/j.bmc.2018.04.015

Experimental method

X-RAY DIFFRACTION (1.95 Å)