Computational identification of potential modulators of heme-regulated inhibitor (HRI) for pharmacological intervention against sickle cell disease

Abstract

Sickle cell disease (SCD) poses a significant health challenge and therapeutic approaches often target fetal hemoglobin (HbF) to ameliorate symptoms. Hydroxyurea, a current therapeutic option for SCD, has shown efficacy in increasing HbF levels. However, concerns about myelosuppression and thrombocytopenia necessitate the exploration of alternative compounds. Heme-regulated inhibitor (HRI) presents a promising target for pharmacological intervention in SCD due to its association with HbF modulation. This study screened compounds for their potential inhibitory functions against HRI. Small-molecule compounds from 17 folkloric plants were subjected to in silico screening against HRI. Molecular docking was performed, and free binding energy calculations were determined using molecular mechanics with generalized born and surface area (MMGBSA). Lead compounds were subjected to molecular dynamics simulation at 100 ns. Computational quantum mechanical modeling of the lead compounds was subsequently performed. We further examined the pharmacodynamics, pharmacokinetic and physiological properties of the identified compounds. Five potential HRI inhibitors, including kaempferol-3-(2G-glucosyrutinoside), epigallocatechin gallate, tiliroside, myricetin-3-O-glucoside and cannabiscitrin, with respective docking scores of −16.0, −12.17, −11.37, −11.56 and 11.07 kcal/mol, were identified. The MMGBSA analysis of the complexes yielded free-binding energies of −69.76, −71.17, −60.44, −53.55 and −55 kcal/mol, respectively. The identified leads were stable within HRI binding pocket for the duration of the 100 ns simulation. The study identified five phytoligands with potential inhibitory effects on HRI. This finding holds promise for advancing SCD treatment strategies. However, additional preclinical analyses are warranted to validate the chemotherapeutic properties of the lead compounds.

Communicated by Ramaswamy H. Sarma

Keywords:

• Sickle cell
• fetal hemoglobin
• heme-regulated inhibitor
• molecular docking
• MMGBSA

Acknowledgements

The authors appreciate students and scientists at the Center for Genomic Research in Biomedicine (CeGRIB), Mountain Top University for the clerical support during manuscript drafting.

Authors’ contributions

AJO and KMO conceived and designed the study. AJO and AO implemented in silico modeling. AJO, SOO and KMO drafted the manuscript. All authors read, revised and approved the final manuscript.

Consent for publication

Not applicable.

Disclosure statement

No potential conflict of interest was reported by the authors.

Ethics approval and consent to participate

Not applicable.

Availability of data and materials

The dataset supporting the conclusions of this article are within the manuscript and its Additional Files 1 and 2. The link to the script used in generating plots and graphs can be found here.

Additional information

Funding

Kolapo Oyebola was supported by Fogarty Emerging Global Leader Grant (NIH-K43TW011926) from the US National Institutes of Health and an APTI-18-07 Grant from the African Academy of Sciences in partnership with Bill and Melinda Gates Foundation. The funders had no role in study design, data collection, analysis, decision to publish or preparation of the manuscript.