Title : Potential bruton tyrosine kinase (BTK) inhibitors determined by virtual screening, molecular docking, and molecular dynamics simulation studies
Abstract:
Bruton tyrosine kinase (BTK) is a downstream mediator of the B cell receptor (BCR) signalling pathway and affects B cell proliferation and differentiation. Evidence showing BTK expression in the majority of hematological cells has led to the hypothesis that BTK inhibitors such as ibrutinib may be an effective treatment for leukemias and lymphomas. However, increasing experimental and clinical data have revealed the importance of BTK not only in B-cell malignancies but also in solid tumours such as breast, ovarian, colorectal and prostate cancers. Additionally, increased BTK activity is associated with autoimmune diseases. This has led to the hypothesis that BTK inhibitors may be useful in the treatment of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), Sjögren's syndrome (SS), allergy and asthma. Recently, great efforts have been made to discover new BTK inhibitors. However, a limited number of BTK inhibitors have been designed and approved so far. Among these, ibrutinib, developed by Pharmacyclics and Janssen, was approved by the US FDA for the treatment of mantle cell lymphoma (MCL) in November 2013 and chronic lymphocytic leukemia (CLL) in February 2014, respectively. Ibrutinib is a selective and irreversible BTK inhibitor that forms a covalent bond with a non- conserved cysteine residue (Cys481) proximal to the active site of BTK. As an ATP-competitive inhibitor, ibrutinib binds to the ATP-binding pocket of BTK and prevents autophosphorylation of Tyr223, abolishing full activation of BTK, which culminates the signal transduction cascade. It is noteworthy that ibrutinib is the first and only FDA-approved BTK inhibitor so far. Despite its unprecedented success, acquired resistance to ibrutinib has been observed in patients with CLL and MCL. Based on this situation, there is an urgent need to discover BTK inhibitors with new chemical scaffolds. Virtual screening, an effective tool, is important in drug development studies. Therefore, this study aimed to use computer-assisted approaches to identify potential inhibitors of BTK. A virtual screening, molecular docking, and molecular dynamics (MD) simulation and MM/GBSA calculations carried out to identify hit candidates for the treatment of BTK target-related diseases. MD Simulations showed the binding interactions between the identified molecules and BTK. This information will use to design and optimize new inhibitors with improved binding properties and stability. The findings obtained from this study will also emphasize the importance of computational
methods in drug discovery.
Audience Take Away Notes:
- Potential BTK inhibitors determined by in silico methods can lead to pre-clinical in vitro and/or in vivo studies that can benefit researchers working in this field
- It is thought that the results we obtained will be guiding for further studies
- This study will make a significant contribution to the literature with our drug discovery studies
