New predicted dual CDK-2/CDK-1 inhibitors from Aspergillus unguis isolate SP51-EGY with relative selectivity for colorectal cancer cells: a computational and experimental approach

Abstract Colorectal cancer is one of the deadliest cancers in the world. The main problem with cancer treatments is that they need to protect healthy cells. Cyclin-dependent kinases (CDKs), especially CDK-2 and CDK-1, are essential for regulating the cell cycle, cell growth, and tumor genesis. Their dysregulation is frequently detected in colorectal cancer, resulting in uncontrolled cell division and resistance to apoptosis, making them attractive targets for anticancer therapy. The fungal " Aspergillus unguis isolate SP51-EGY" “Sh cell” (shake mycelia) extract had the most significant cytotoxic action against HCT116 cancer cells (IC 50 = 3.49 µg/mL) and a selectivity index (SI = 23.33), indicating relative cytotoxicity against cancer cells. Computational modeling and cellular phenotypic data suggest a potential mechanism of dual CDK2/1 inhibition, forming a testable hypothesis that requires direct enzymatic validation. Compounds corresponding to peaks 7 and 14 have been tentatively assigned as promising CDK inhibitors based on molecular docking studies; due to their: (1) strong binding affinities (-13.23 to -46.05 kcal/mol) confirmed by stable molecular dynamics (RMSD < 2.0 Å); (2) cell cycle arrest mediated by dual CDK2/1 inhibition; and (3) favorable drug-like properties, such as molecular weight < 500 Da, good intestinal absorption, and minimal toxicity. Critical interactions with CDK2 (Tyr16, Phe81) and CDK1 (Met88) active site residues were identified by structural analysis. These interactions competed with ATP to disrupt the CDK2 cyclin A and CDK1/cyclin A/B complexes, which resulted in both G1/S and G2/M cell cycle arrests. These integrated computational and cellular findings suggest that the fungal-derived compounds are promising candidates for novel dual CDK2/CDK1 inhibitors, warranting further experimental validation through biochemical kinase assays.