Deciphering pH-Driven Dynamics of Prolyl Endopeptidases: Unveiling Structural insight in Celiac Disease using Computational Techniques

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Celiac disease, an intricate autoimmune disorder, stems from gluten consumption, primarily found in wheat, barley, and rye. Due to its high proline content, resists complete breakdown the human digestive system. Prolyl endopeptidases (PEPs), a subclass of serine proteases, offer promising therapeutic avenue. These enzymes exhibit unique ability cleave peptide bonds post residues, aiding digestion. However, leveraging these effectively mandates profound understanding their operation within dynamic pH milieu gastrointestinal tract. This study delves into influence variations on PEP structure activity, employing advanced computational methodologies. The research initiates with acquiring sequences ten diverse organisms via UniProt database. Employing sequence analysis techniques like multiple alignment pairwise alignment, we identify pH-sensitive regions by scrutinizing conserved motifs disparities. Prot Pi facilitates computation net charge profiles across varied gradients, unveiling pH-responsive distribution patterns. Structural involves predicting 3D conformations through Pep-Fold4, encapsulating protein adaptations fluctuations. RMSD calculations PyMOL reveal pH-induced conformational alterations implications for stability. Also, rigorous homologous modeling PEPs Swiss Model ensures structural fidelity, energy optimization YASARA refines geometric parameters, while ERRAT validates integrity. Docking simulations forecast PEP-gluten interactions conditions. In conclusion, our comprehensive data provides novel insights how modulates structures. findings bear significant enzyme catalysis, resilience, potential strategies.

Language: Английский

In-Silico Identification and Evaluation of Diosgenin as a Promising Phytomedicine Targeting MHC-I for Cancer Therapy

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 26, 2025

Immunotherapeutic strategies targeting MHC-I have gained significant attention for combating cancer, a leading global health. However, the emergence of therapeutic resistance and manifestation adverse concerneffects associated with conventional treatment modalities underscore imperative innovative strategies. In current study, we conducted an “in silico”investigation to identify potential phytomedicines cancer (3AM8). Using AutodockTools software, 408 natural secondary polyphenols were screened against MHC-I, Diosgenin exhibiting highest affinity binding (−8.93 Kcal/mol). Pharmacokinetic profiling highest-ranking ligands elucidated their suitability subsequent development optimization. Molecular dynamics simulations, using Desmond software suite, demonstrated pronounced stability Diosgenin-MHC-I complex throughout 100-ns trajectory. Our findings suggest that holds promise as candidate therapeutics; however, further verifications by use extensive vitro” vivo”research is warranted substantiate its validity potential. This study highlights in upcoming trial regimens advances choices treating cancer.

Language: Английский