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BackgroundSickle cell disease (SCD) poses a signi cant health challenge and therapeutic approaches often target fetal hemoglobin (HbF) to ameliorate symptoms. Hydroxyurea, a current therapeutic option for SCD, has shown e cacy 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. MethodsSmall-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 identi ed compounds. ResultsFive potential HRI inhibitors, including kaempferol-3-(2G-glucosyrutinoside), epigallocatechin gallate, tiliroside, myricetin-3-Oglucoside, and cannabiscitrin, with respective docking scores of -16.0, -12.17, -11.37, -11.56 and 11.07 kcal/mol, were identi ed. 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 identi ed leads were stable within HRI binding pocket for the duration of 100 ns simulation. ConclusionsThe study successfully identi ed ve phytoligands with potential inhibitory effects on HRI, opening avenues for their use as modulators of HbF in SCD patients. This nding holds promise for advancing treatment strategies in SCD. However, additional preclinical analyses are warranted to validate the chemotherapeutic properties of the lead compounds.
BackgroundSickle cell disease (SCD) poses a signi cant health challenge and therapeutic approaches often target fetal hemoglobin (HbF) to ameliorate symptoms. Hydroxyurea, a current therapeutic option for SCD, has shown e cacy 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. MethodsSmall-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 identi ed compounds. ResultsFive potential HRI inhibitors, including kaempferol-3-(2G-glucosyrutinoside), epigallocatechin gallate, tiliroside, myricetin-3-Oglucoside, and cannabiscitrin, with respective docking scores of -16.0, -12.17, -11.37, -11.56 and 11.07 kcal/mol, were identi ed. 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 identi ed leads were stable within HRI binding pocket for the duration of 100 ns simulation. ConclusionsThe study successfully identi ed ve phytoligands with potential inhibitory effects on HRI, opening avenues for their use as modulators of HbF in SCD patients. This nding holds promise for advancing treatment strategies in SCD. However, additional preclinical analyses are warranted to validate the chemotherapeutic properties of the lead compounds.
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.
Spondias mombin (S. mombin), a prominent botanical resource, has garnered recognition within folkloric therapy. Parkinson's disease (PD), characterized by dopaminergic neuron attrition in the substantia nigra, manifests as motor anomalies like tremors, rigidity, and bradykinesia. This study capitalizes on S. mombin's reservoir of 100 characterized phytocompounds and employs computational methodologies to interrogate their potential 35 PD-associated target proteins. Employing a multifaceted approach, we engaged in molecular docking, ADMET predictions, Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) evaluations, Density Functional Theory (DFT), and Molecular Dynamic Simulations (MDS). This comprehensive framework facilitated insightful structural assessments and predictive analyses. Impressively, flavonoids hailing from S. mombin, including quercetin, catechin, ellagic acid, and epicatechin, showcased optimal binding affinities for PD-relevant target proteins. Moreover, these identified ligands exhibited minimal signs of mutagenicity, tumorigenicity, or irritancy, except for quercetin, which displayed elevated tumorigenic potential. Notably, quercetin and dopamine exhibited varying band gap energies, with quercetin the lowest (3.63 eV) and dopamine the highest (5.76 eV) values. MDS result suggests a synergistic outcome based on the RMSD and RMSF graphs for quercetin highlighting it as the best of all including the co-ligand. In a collective sense, our findings present S. mombin as promising reservoirs of active pharmaceutical ingredients, warranting further exploration for novel PD therapeutic avenues. Consequently, this study underscores the enhanced efficacy of phyto-ligands sourced from S. mombin, advocating their optimization as potential drug candidates.
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