The PI3K-AKT-mTOR pathway is often a commonly disrupted pathway in human cancer and, therefore, it is widely exploited for cancer therapy. The inhibitors for the important proteins of the pathway including PI3K and mTOR have been increasingly designed. The dual inhibitors targeting PI3K and mTOR both have proven to be more effective than those targeting single protein only. An orally-active compound XL765 is well established as PI3K/mTOR dual inhibitor and have shown in vitro and in vivo anticancer activity against a variety of cancer types and is undergoing clinical trials. The present study explored the exact binding pose and the the interactive forces holding XL765 within the active sites of PI3Kγ and mTOR using molecular docking analyses. The XL765 interacting residues of both the proteins were delineated and the degree of participation in binding was estimated by various methods. In the process, among the interacting residues of PI3Kγ, the Lys-890 and the Met-953 were recognized as the key residues involved in XL765 binding. While, in mTOR case, the Trp-2239 was recognized as the key residue playing role in the XL765 binding. In order to explore the better inhibitors, the study also generated combinatorial chemical library by modifying the scaffold considered from XL765. The virtual screening of the generated compound library led to identification of six novel promising compounds proposed as PI3K/mTOR dual inhibitors. Thus, the present work will through light on the drug inhibitory mechanism of XL765 for PI3K and mTOR, and will also assist in designing novel efficacious drug candidates.