Computational identification of potential modulators of heme-regulated inhibitor (HRI) for pharmacological intervention against sickle cell disease.
| العنوان: | Computational identification of potential modulators of heme-regulated inhibitor (HRI) for pharmacological intervention against sickle cell disease. |
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| المؤلفون: | Owoloye AJ; Mountain Top University., Olubode SO; Adekunle Ajasin University Akungba., Ogunleye A; University of Würzburg., Idowu ET; University of Lagos., Oyebola KM; Mountain Top University. |
| المصدر: | Research square [Res Sq] 2023 Dec 15. Date of Electronic Publication: 2023 Dec 15. |
| نوع المنشور: | Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101768035 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: Res Sq Subsets: PubMed not MEDLINE |
| مستخلص: | Background: 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 systematically screened compounds for their potential inhibitory functions against HRI. Methods: Small-molecule compounds from 17 plants commonly utilized in traditional SCD management 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). The lead compounds were subjected to molecular dynamics simulation at 100 ns. Computational quantum mechanical modelling of the lead compounds was subsequently performed. We further examined the pharmacodynamics, pharmacokinetic and physiological properties of the identified compounds. Results: 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 100 ns simulation. Conclusions: The study successfully identified five phytoligands with potential inhibitory effects on HRI, opening avenues for their use as modulators of HbF in SCD patients. This finding holds promise for advancing treatment strategies in SCD. However, additional preclinical analyses are warranted to validate the chemotherapeutic properties of the lead compounds. Competing Interests: Competing Interests Authors declare no competing interests. |
| التعليقات: | Update in: J Biomol Struct Dyn. 2024 Mar 31;:1-13. (PMID: 38555858) |
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| معلومات مُعتمدة: | K43 TW011926 United States TW FIC NIH HHS |
| فهرسة مساهمة: | Keywords: Fetal hemoglobin; Heme-regulated inhibitor; MMGBSA; Molecular docking; Sickle cell |
| تواريخ الأحداث: | Date Created: 20240103 Latest Revision: 20240408 |
| رمز التحديث: | 20240408 |
| مُعرف محوري في PubMed: | PMC10760220 |
| DOI: | 10.21203/rs.3.rs-3755458/v1 |
| PMID: | 38168168 |
| قاعدة البيانات: | MEDLINE |
| DOI: | 10.21203/rs.3.rs-3755458/v1 |
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