Protein kinases play quintessential roles in regulating various cellular processes. Aberrant activation of their signal transduction modules contribute to diverse ailments including cancer. Kinases, therefore, have become attractive drug targets for therapeutic intervention. Majority of kinases are classified into the two most widely acknowledged families encompassing serine/threonine and tyrosine kinases. The mTOR (mammalian Target of Rapamycin) is a serine/threonine kinase that regulates fundamental processes including protein synthesis, growth, metabolism, aging, regeneration, and autophagy. RET (REarranged during Transfection) is a transmembrane receptor tyrosine kinase required to maintain the neuronal populations of peripheral, sympathetic, parasympathetic, and enteric nervous systems. The molecules targeting both serine/threonine and tyrosine kinases possess potent antitumor activity and have demonstrated clinical efficacy. The clinical success of PP121, a dual inhibitor of mTOR and RET kinase, therefore, was explored in the present investigation. Correspondingly, an auto-pharmacophore model was generated and employed to screen four databases of natural molecules, which map the features observed for PP121. Within this framework, multiple computational approaches were integrated including homology modeling, molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations. The hierarchical strategy led to identification of two compounds- STOCK1N-98911 and STOCK1N-84953, which bind to ATP-binding sites as well as allosteric sites, of mTOR and RET kinase. Free energy calculations highlighted the role of vital residues contributing to favorable interactions in binding of hits with mTOR and RET kinase. The pharmacokinetic properties of hits were also evaluated in silico to ensure their bioavailability, providing a rationale for their development as leads against both kinases. Altogether, this investigation provides a preliminary platform for future experimental research, towards the development of dual inhibitors of serine/threonine and tyrosine kinases, a persuasive strategy for intersecting two families of oncogenes.