Comparative Molecular Docking Analysis of Evobrutinib and Orelabrutinib targeting BTK in Multiple Sclerosis
Comparative Molecular Docking Analysis of Evobrutinib and Orelabrutinib targeting BTK in Multiple Sclerosis
Melika Naderi,1,*
1. Islamic Azad University Pharmaceutical Sciences Branch
Introduction: Multiple Sclerosis (MS) is a chronic autoimmune disease in relation with the central nervous system (CNS). It’s believed that cells from either innate or adaptive immune pathways are in charge of the development and progression of the disease. The Bruton's tyrosine kinase (BTK) is a key enzyme, being present in many cells, has been recognized as a potential target for MS treatment. In fact, BTK has a pivotal role in activating immune cells, particularly glial cells and B cells, causing the production of pro-inflammatory cytokines. Extensive studies have indicated that BTK inhibitors can both modulate B-cell function, in order to reduce inflammation and autoantibody production, and regulate immunomodulatory effects of glial cells, including astrocytes and microglia. Moreover, BTK inhibitors have shown promising outcomes in preclinical studies by decreasing demyelination, which is another hallmark in MS pathogenesis. The purpose of this study is to compare the effect of two selective BTK inhibitor, Evobrutinib and Orelabrutinib, on BTK activity. May this survey shed light on the exploration of novel therapeutic agents for the treatment of MS.
Methods: In this research, at first, the BTK structure was downloaded from the Uniprot website, then necessary preparations, including adding charge and hydrogen ions, were performed using Chimera software. The three-dimensional structures of Evobrutinib and Orelabrutinib were obtained from the PubChem website. The binding site of the BTK was determined using Deepsite. [Center; X: 8.1341, Y: 14.500, Z: 36.303 and Dimensions (Angstrom); X, Y, Z: 25.00] Finally, the molecular docking process was operated using AutoDock Vina in PyRx 0.8 to investigate the binding status of Evobrutinib and Orelabrutinib to BTK.
Results: Following the completion of the docking process of Evobrutinib and Orelabrutinib with BTK, using PyRx software, the achieved results are summarized below. For each Model, the data represents their binding affinity, RMSD lower bond and RMSD upper bound, respectively:
Evobrutinib:
Model #1: [-5.7, 0.0, 0.0]
Model #2: [-5.5, 0.0, 0.0]
Model #3: [-5.4, 1.603, 2.237]
Orelabrutinib:
Model #1: [-5.2, 0.0, 0.0]
Model #2: [-4.7, 24.23, 26.577]
Model #3: [-4.6, 4.434, 6.022]
Conclusion: Based on the findings from the molecular docking analysis of Evobrutinib and Orelabrutinib with BTK, it has been determined that both drugs exhibit negative binding energy. Furthermore, Evobrutinib demonstrated a greater affinity in comparison with Orelabrutinib. Given the data presented in this research, is more likely that Evobrutinib holds promise as a potential treatment option for MS when compared to Orelabrutinib; nevertheless, additional investigation is still needed regarding BTK inhibitors.