In silico analysis of a novel protein in CAR T- cell therapy for the treatment of hematologic cancer through molecular modelling, docking, and dynamics approach

Cellular therapy has emerged as a key tool in the treatment of hematological malignancies. An advanced cell therapy known as chimeric antigen receptor T cell therapy (CAR T-cell therapy) has been approved by the United States Food and Drug Administration (FDA) as KYMRIAH by Novartis and YESCARTA by Gilead/Kite pharma in the year 2017. A chimeric receptor is composed of an extracellular antigen recognition site along with some costimulating and signalling domains. On the whole, it turns out to be one of the most potent receptors on T cells targeting a specific type of cancer cell based on its antigenic marker. CD19 CAR T-cell therapy is the first clinically approved therapy for lymphoma with remarkable results in complete remission of B cell lymphoblastic leukemia up to 90%. The high rate of effectiveness of the CAR T-cell therapy against B-ALL justifies the investigation and application of this therapy for fatal diseases like all types of hematological malignancies. The most critical aspect of chimeric receptor therapy is designing and building an artificial receptor that is specific to a given type of cancer. For this reason, the in silico technique is an appropriate model to investigate the integrity and effectiveness of the engineered chimeric receptor prior to commencing in vitro experiments followed by clinical trials. This computerized experimental study aids in predicting the molecular mechanism of chimeric protein and how it interacts with both ligands. We have anticipated various features of the chimeric protein in terms of qualitative analysis (structure, protein modelling, physiological properties) and functional analysis (antigenicity, allergenicity, its receptor-ligand binding ability, involving signalling pathways). Furthermore, the reliability and validation of the binding mode of the chimeric protein against receptors were performed through a complex molecular dynamics simulation for a 100 ns timeframe in an aqueous environment. The obtained simulation study showed that CD30 was a better approachable marker as compared to CD20 due to its better binding energy score and also binding conformations stability.