Abstract
Sickle cell disease (SCD) is a monogenic blood disorder associated with a mutation in the hemoglobin subunit β gene encoding for the β-globin of normal adult hemoglobin (HbA). This mutation transcribes into a Glu-β6 → 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 antisickling 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, recently proposed as SCD aggregation inhibitors (Neto, V.; J. Med. Chem. 2023, 66, 16062-16074), is enough to turn the dimerization of HbS thermodynamically unfavorable. Among these potential drugs, some exhibit an estimated pocket abandonment probability of around 15-20% within the simulations' time frame, and an impressive specificity toward the mutated Val-β6. Additionally, we show that the dimerization can be thermodynamically unfavored by blocking a nearby region while the pocket remains vacant. 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 cyclic peptides as antisickling drug candidates to reduce the concentration of aggregation-competent HbS.