In silico screening of phytochemicals against chromatin modifier, SETD7 for remodeling of the immunosuppressive tumor microenvironment in renal cancer

The tumor microenvironment and immune evasion function in a complex cellular network profoundly challenge the clinical outcome of promising therapies. Our recently published study reported that the subset of genes upregulated in ccRCC due to H3K4me1 and DNA demethylation potentially leads to an immunosuppressive environment. Thus, modulating H3K4me1 chromatin modifier SETD7 with a natural inhibitor in combination with immunotherapy might improve the immune landscape for a better therapeutic outcome. The present study was conducted via virtual screening and MD simulation using compounds from the literature, IMPPAT, and SuperNatural database. The phytochemical IMPHY002979 showed better binding affinity and lower energy than the reported R-PFI-2 and cyproheptadine inhibitors. The phytochemicals interact with the SET domain through H-bonding, as confirmed by MD simulation and molecular interaction analysis. Further, the compound was assessed using ADME parameters and free energy estimation, showing better pharmacokinetic properties. Therefore, the non-accessibility of the histone methyltransferase activity domain of SET7 with IMPHY002979 can downregulate H3K4me1 and, thereby, the expression of genes potentially responsible for immunosuppressive TME. Thus, patient stratification based on molecular markers for immunotherapy and combining epigenetic modulators with therapeutic drugs will improve the efficacy of immunotherapy in ccRCC.