Discovering Dually Active Anti-cancer Compounds with a Hybrid AI-structure-based Approach

: Cancer's persistent growth often relies on its ability to maintain telomere length and tolerate the accumulation of DNA damage. This study explores a computational approach to identify compounds that can simultaneously target both G-quadruplex (G4) structures and poly(ADP-ribose) polymerase (PARP)1 enzyme, offering a potential multipronged attack on cancer cells. We employed a hybrid virtual screening (VS) protocol, combining the power of machine learning with traditional structure-based methods. PyRMD, our AI-powered tool, was first used to analyze vast chemical libraries and to identify potential PARP1 inhibitors based on known bioactivity data. Subsequently, a structure-based VS approach selected compounds from these identified inhibitors for their G4 stabilization potential. This two-step process yielded 50 promising candidates, which were then experimentally validated for their ability to inhibit PARP1 and stabilize G4 structures. Ultimately, four lead compounds emerged as promising candidates with the desired dual activity and demonstrated antiproliferative effects against specific cancer cell lines. This study highlights the potential of combining Artificial Intelligence and structure-based methods for the discovery of multitarget anticancer compounds, offering a valuable approach for future drug development efforts.