Molecular mechanics and dynamics simulation of CD-47/SIRPα blockade study: A computational study on overcoming immunotherapeutic resistance in pancreatic ductal adenocarcinoma

Abstract

The sting of pancreatic ductal adenocarcinoma remains an irksome burden to the human populace. The focus of recent research has switched from finding the perfect medicinal medication to blocking immunological checkpoint proteins such as the signal regulating protein alpha-cluster of differentiation 47 (SIRPα-CD47). The search for CD47/SIRPα inhibitors with excellent oral bioavailability and permeability continues to elude researchers. This research aims to identify bioactive molecules with negligible side as inhibitor SIRPα-CD47 signaling cascade. Bioactive flavonoids from African medicinal plants were virtually screened against the SIRP-α binding site of CD47 using Schrodinger suite 2017-v1. The docking score was validated and complex stability performed using Gromacs. Among the bioactive flavonoids, five (5) compounds were predicted as potent inhibitors of CD47 with pelargonidin observed to have the best binding affinity of −6.715 kcal/mol. Validation using QSAR and pharmacophore modeling further confirm the interaction with predicted pIC50 range of 5.981 to 6.841 µM and fitness score of 1.109 to 1.530. Drug-likeness prediction revealed that all hit compounds obey Lipinski’s rule of five. The MD simulation result predicted the stability of pelargonidin and malvidin comparable to the standard drug NCGC00138783. The quantum mechanics estimation revealed that, the hit compounds have proton donating and accepting ability hence, they possess inhibitory potential. From the molecular docking, post-docking and MD simulation analyzes of this study, Pelargonidin, malvidin and Peonidin were proposed as suitable candidates that could be probed further for developing a new target-specific immunotherapeutic agent against PDAC.