Fig. 8: Workflow for generating and screening molecules, including MTT assay and inhibitory effects of selected lead compounds.
a Workflow for virtual screening of the molecules generated by the ClickGen model to identify lead compounds. The screening workflow involves filtering generated molecules based on novelty, validity, redundancy, and scaffold similarity, followed by physicochemical property assessment and pharmacophore matching to select molecules capable of forming key hydrogen bonds. These molecules underwent docking simulations, and the top 1% based on docking scores were clustered by scaffold. Clusters were evaluated comprehensively, considering similarity to known PARP1 inhibitors, synthetic accessibility, and intellectual property potential. Compounds were categorized into low, medium, and high synthetic difficulty based on raw material availability and reaction complexity. After rigorous evaluation of synthesis routes, three lead molecules, spanning different synthetic challenges, were identified for further investigation; b The MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay (n = 3) results showing the effects of the three lead compounds and the positive control on Human lung adenocarcinoma (A549), human ovarian (OVCAR-3), human colon (HCT-116), and human colon (MCF-7) cancer cell lines; c The inhibitory effects of the three lead compounds and the positive control on PARP-1 enzyme activity (n = 3). In the curves of subplots b and c, the dots represent the mean IC50 values from three independent measurements, and the error bars indicate the standard deviation (SD), and detailed mean ± SD raw data of IC50 are recorded in the source data.
