Journal of Advanced Biomedical Sciences

en ارزیابی درون‌سیلیکویی انتخاب‌پذیری کنفورماسیونی مشتقات کورکومین و رزمارینیک اسید برای حالت‌های Tense و Relaxed هموگلوبین داسی‌شکل In Silico Evaluation of the Conformational Selectivity of Curcumin and Rosmarinic Acid Derivatives for Tense and Relaxed States of Sickle Cell Hemoglobin داروسازي و فارماکولوژِی Pharmacology پژوهشي Research <div style="text-align: justify;">Background & Objective: Sickle cell disease (SCD) arises from the polymerization of hemoglobin S (HbS) under low-oxygen conditions, leading to vaso-occlusion and organ damage. This study evaluated the binding and interaction profiles of curcumin and rosmarinic acid in comparison with voxelotor across different HbS conformations. Materials & Methods: Molecular docking was performed using Molegro Virtual Docker (MVD) with the MolDock Scoring algorithm. Two HbS models were used: the relaxed state (PDB ID: 5E83) and the tense state (PDB ID: 2HBS). The docking protocol was validated by redocking the co-crystallized ligand, with an RMSD threshold of < 3.8 Å. Binding affinities were compared between the R2 and T states to assess conformational selectivity. Results: Analysis of ligand-binding profiles in the R2 (−149.57) and T (−118.84) conformations of HbS revealed marked differences. Rosmarinic acid and curcumin preferentially bound to the R2 state, as indicated by their more favorable binding scores, greater hydrogen-bonding interactions, and interaction energies. Voxelotor also exhibited a more favorable score in R2 than in T (−122.39 vs. −109.27). Although the T state exhibited stronger individual interactions, the overall interaction profiles were less extensive. In contrast, the R2 state provided a more favorable binding environment for multiple ligands. The findings are consistent with the Monod-Wyman-Changeux allosteric model and suggest that the R2 state provides a more favorable physicochemical environment for ligand accommodation. The transition from T to R2 involves a redistribution of energetic hotspots, with the principal interactions for rosmarinic acid shifting from Arg141 and Thr137 toward Lys99 and His103. These findings highlight the importance of steric complementarity and van der Waals forces, in addition to hydrogen bonding, in effective allosteric stabilization. Conclusion: This study suggests that the R2 conformation of HbS provides a more favorable binding environment for the investigated natural polyphenols and synthetic ligands. These results provide a computational basis for designing novel antisickling agents that selectively stabilize the relaxed state to mitigate SCD pathology.</div> Sickle Cell Disease, Hemoglobin S, Molecular Docking, Protein Conformation, Curcumin 0 0 http://jabs.fums.ac.ir/browse.php?a_code=A-10-3547-1&slc_lang=en&sid=1 Roohallah Yousefi روح الله یوسفی r.yosefi@modares.ac.ir 100319475328460031130 100319475328460031130 No Department of Biochemistry, Faculty of Biology, Tarbiat Modares University of Tehran, Tehran, Iran گروه بیوشیمی، دانشکده علوم زیستی، دانشگاه تربیت مدرس، تهران، ایران seyed Hossein Khaleghinejad سید حسین خالقی نژاد hosseinkhaleghi89@yahoo.com 100319475328460031131 100319475328460031131 Yes Department of Bioinformatics and Applied Biotechnology, Faculty of Biotechnology, Amol University of Special Modern Technologies, Amol, Iran گروه بیوانفورماتیک و زیست‌فناوری کاربردی، دانشکده زیست‌فناوری، دانشگاه تخصصی فناوری‌های نوین آمل، آمل، ایران Dariush Gholami داریوش غلامی d.gholami@ausmt.ac.ir 100319475328460031132 100319475328460031132 No Department of Bioinformatics and Applied Biotechnology, Faculty of Biotechnology, Amol University of Special Modern Technologies, Amol, Iran گروه بیوانفورماتیک و زیست‌فناوری کاربردی، دانشکده زیست‌فناوری، دانشگاه تخصصی فناوری‌های نوین آمل، آمل، ایران Sadegh Hasannia صادق حسن نیا hasannia@modares.ac.ir 100319475328460031133 100319475328460031133 No Department of Biochemistry, Faculty of Biology, Tarbiat Modares University of Tehran, Tehran, Iran گروه بیوشیمی، دانشکده علوم زیستی، دانشگاه تربیت مدرس، تهران، ایران