![Author ORCID: We display the ORCID iD icon alongside authors names on our website to acknowledge that the ORCiD has been authenticated when entered by the user. To view the users ORCiD record click the icon. [opens in a new tab]](https://chemrxiv.org/engage/assets/public/chemrxiv/images/logos/orcid.png)
Abstract
Sickle cell disease is a monogenic blood disorder associated with a mutation in the HBB gene encoding for the β-globin of normal adult hemoglobin (HbA). This mutation transcribes into a Gluβ6→Val-β6 substitution in the β-globins, inducing the polymerization of this hemoglobin form (HbS) when in the T-state. Despite advances in stem cell and gene therapy and the recent approval of a new anti-sickling drug, therapeutic limitations persist. Herein, we demonstrate through molecular dynamics and umbrella sampling, that (unrestrained) blockage of the hydrophobic pocket involved in the lateral contact of the HbS fibers by 5-mer cyclic peptides (CPs) recently proposed as SCD aggregation inhibitors (J. Med. Chem. 2023, 66, 16062), is enough to turn the dimerization of HbS thermodynamically unfavorable. Amongst these potential drugs, some exhibit an estimated pocket abandonment probability of around 15-20% within the simulations’ timeframe, and an impressive specificity towards the mutated Val-β6. Additionally, we show that the dimerization can be thermodynamically unfavored by blocking a nearby region while the pocket remains undrugged. These results are compared with curcumin, an antisickling molecule and a pan-assay interference compound, with a good binding affinity for different proteins and protein domains. Our results confirm the potential of some of these CPs as anti-sickling drugs to reduce the concentration of aggregation-competent HbS.
Supplementary materials
Title
Supporting Information
Description
Figure S1 – PMF for the 2HbS dimer from the first half the last half of the umbrella sampling trajectories.
Figure S2 – Moving average of the RMSD of 2HbS, HbS-1, HbS-2, and the monomers of HbS and HbA.
Figure S3 – HbS–HbS mean distances as a function of the mean values of the reaction coordinate.
Figure S4 – PMF calculated from the last 10 ns of the umbrella sampling trajectories.
Figure S5 – The last snapshot of the umbrella sampling trajectories for the window = 0.5 nm, and the moving average of the pocket-CP minimum distance, for VVVVV, VFVFV, and VKVKV.
Actions
