De Novo Design and In Silico Validation of New Inhibitors Against PIKfyve as a Treatment for Cancer and Viral Diseases

ABSTRACT The phosphatidylinositol 3‐phosphate 5‐kinase (PIKfyve), is a key enzyme in the phosphoinositide signaling pathway, which plays a crucial role in the development of various cancers and viral diseases. The essential role of small molecules that inhibit this enzyme is limited, which further complicates the design of effective and selective inhibitors. In this study, we employed a BREED‐based de novo ligand design strategy after the detection of a binding pocket in PIKfyve. The BREED‐based molecules were subjected to pharmacokinetic and docking studies. From molecular dynamics (MD) simulations, the hit molecules were observed to exhibit stable behavior in complex with the protein and retain favorable interactions at the binding site. These molecules were also assessed on the synthesizability scale, through reaction‐based enumeration, to determine their ease of synthesis. Overall, the study undertaken describes a de novo hybridization approach that automates the inhibitor design process to reduce the time for producing reliable results when there is limited information about inhibitors in the literature. The selected candidate molecules reveal molecular insights into the inhibition mechanism of PIKfyve.