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Inverse Molecular Docking as a Novel Approach to Study Anticarcinogenic and Anti-Neuroinflammatory Effects of
Veronika Furlan1, Janez Konc2, Urban Bren3,4
1Faculty of Chemistry and Chemical Technology, University of Maribor, Smetanova 17, SI-2000 Maribor, Slovenia. veronika.furlan@um.si.
Abstract:
Research efforts are placing an ever increasing emphasis on identifying signal transduction pathways related to the chemopreventive activity of curcumin. Its anticarcinogenic effects are presumably mediated by the regulation of signaling cascades, including nuclear factor κB (NF-κB), activator protein 1 (AP-1), and mitogen-activated protein kinases (MAPK). By modulating signal transduction pathways, curcumin induces apoptosis in malignant cells, thus inhibiting cancer development and progression. Due to the lack of mechanistic insight in the scientific literature, we developed a novel inverse molecular docking protocol based on the CANDOCK algorithm. For the first time, we performed inverse molecular docking of curcumin into a collection of 13,553 available human protein structures from the Protein Data Bank resulting in prioritized target proteins of curcumin. Our predictions were in agreement with the scientific literature and confirmed that curcumin binds to folate receptor β, DNA (cytosine-5)-methyltransferase 3A, metalloproteinase-2, mitogen-activated protein kinase 9, epidermal growth factor receptor and apoptosis-inducing factor 1. We also identified new potential protein targets of curcumin, namely deoxycytidine kinase, NAD-dependent protein deacetylase sirtuin-1 and -2, ecto-5'-nucleotidase, core histone macro-H2A.1, tyrosine-protein phosphatase non-receptor type 11, macrophage colony-stimulating factor 1 receptor, GTPase HRas, aflatoxin B1 aldehyde reductase member 3, aldo-keto reductase family 1 member C3, amiloride-sensitive amine oxidase, death-associated protein kinase 2 and tryptophan-tRNA ligase, that may all play a crucial role in its observed anticancer effects. Moreover, our inverse docking results showed that curcumin potentially binds also to the proteins cAMP-specific 3',5'-cyclic phosphodiesterase 4D and 17-β-hydroxysteroid dehydrogenase type 10, which provides a new explanation for its efficiency in the treatment of Alzheimer's disease. We firmly believe that our computational results will complement and direct future experimental studies on curcumin's anticancer activity as well as on its therapeutic effects against Alzheimer's disease.
Insights
This study used computational methods to identify new protein targets for curcumin, revealing its potential anticancer and Alzheimer's disease therapeutic mechanisms. These findings guide future research into curcumin's biological activities.
Area of Science:
- Computational chemistry
- Molecular docking
- Pharmacology
Background:
- Curcumin exhibits chemopreventive and anticancer properties, potentially through modulating signal transduction pathways like NF-κB, AP-1, and MAPK.
- The precise molecular targets and mechanisms underlying curcumin's effects remain incompletely understood.
- Existing research emphasizes the need for mechanistic insights into curcumin's biological activities.
Purpose of the Study:
- To identify novel protein targets of curcumin using a computational approach.
- To elucidate potential molecular mechanisms of curcumin's anticancer and Alzheimer's disease therapeutic effects.
- To provide a computational foundation for future experimental validation of curcumin's targets.
Main Methods:
- Development of a novel inverse molecular docking protocol based on the CANDOCK algorithm.
- Execution of inverse molecular docking of curcumin against 13,553 human protein structures from the Protein Data Bank.
- Prioritization of potential curcumin-protein interactions based on docking scores and literature validation.
Main Results:
- Validated known curcumin targets including folate receptor β, DNA methyltransferase 3A, and MAPK9.
- Identified novel potential anticancer targets such as deoxycytidine kinase, SIRT1/2, and EGFR.
- Discovered potential targets for Alzheimer's disease treatment, including PDE4D and HSD17B10.
Conclusions:
- The study successfully identified and prioritized numerous potential protein targets for curcumin using inverse molecular docking.
- Computational findings provide new mechanistic insights into curcumin's anticancer effects and its therapeutic potential in Alzheimer's disease.
- The results serve as a valuable resource to guide and complement future experimental investigations into curcumin's multifaceted biological activities.
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