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Published on: September 30, 2016
New predicted dual CDK-2/CDK-1 inhibitors from Aspergillus unguis isolate SP51-EGY with relative selectivity for
Ahmed A El-Rashedy1,2, Amal Mosad Ibrahim1, Mohamed S Abdel-Aziz3
1Chemistry of Natural and Microbial Products Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, 33 El Buhouth St., Dokki-Giza, 12622, Egypt.
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 (IC50 = 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.
Insights
Fungal extracts show potent anti-colorectal cancer activity by inhibiting key cell cycle regulators, cyclin-dependent kinases (CDKs). These findings suggest novel therapeutic potential for dual CDK2/1 inhibitors derived from natural sources.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide.
- Dysregulation of cyclin-dependent kinases (CDKs), particularly CDK2 and CDK1, is implicated in CRC progression, driving uncontrolled cell proliferation and apoptosis resistance.
- Targeting CDKs presents a promising strategy for CRC therapy, but requires selective inhibitors to minimize toxicity to healthy cells.
Purpose of the Study:
- To investigate the potential of fungal extracts as a source of novel anticancer agents targeting CDKs in colorectal cancer.
- To explore the mechanism of action of promising compounds identified from fungal extracts, focusing on dual CDK2/1 inhibition.
- To evaluate the drug-like properties and potential therapeutic efficacy of these fungal-derived compounds.
Main Methods:
- Cytotoxicity assays were performed using fungal extracts against HCT116 colorectal cancer cells.
- Computational methods, including molecular docking and molecular dynamics simulations, were employed to predict binding affinities and interactions with CDK2 and CDK1.
- Cellular phenotypic analysis was used to assess cell cycle arrest and validate the inhibitory effects of identified compounds.
Main Results:
- The fungal extract 'Aspergillus unguis isolate SP51-EGY' demonstrated significant cytotoxicity against HCT116 cells (IC50 = 3.49 µg/mL) with a high selectivity index (SI = 23.33).
- Molecular docking and dynamics studies identified specific fungal compounds (peaks [7] and [14]) with strong binding affinities to CDK2 and CDK1 active sites, suggesting dual inhibition.
- These compounds induced G1/S and G2/M cell cycle arrest, consistent with dual CDK2/1 inhibition, and exhibited favorable drug-like properties.
Conclusions:
- Fungal-derived compounds from 'Aspergillus unguis isolate SP51-EGY' show significant potential as dual CDK2/1 inhibitors for colorectal cancer treatment.
- The identified compounds exhibit promising cytotoxic activity and favorable pharmacokinetic profiles, warranting further investigation.
- These findings support the development of novel, natural product-based therapeutics targeting cell cycle regulation in cancer.
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