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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.

Here, we explored the benzothiopyranoindole scaffold to develop antiproliferative agents with a polypharmacological profile targeting both G-quadruplex (G4)-structures and Topoisomerase (Topo) I enzyme. In a preliminary optimization phase, compound 1 was selected from an in-house collection as a suitable lead for the rational development of a small library of analogs ( 2 - 5 ). When assayed in NIH's NCI-60 Human Cancer Cell Line In Vitro Screen Program, compound 1 and its demethylated analogue 2 showed significant antiproliferative/cytotoxic activity. Furthermore, results suggested for 1 and 2 a dual mechanism of action, effectively binding and stabilizing G4 structures, while inhibiting the relaxation activity of TopoI and II. Notably, these compounds displayed a certain selectivity toward TopoI. The polypharmacological profile of 1 and 2 was validated in a human colon carcinoma cell line, underscoring their potential as lead candidates for developing novel and efficacious anticancer agents., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)