Inverse Molecular Docking as a Novel Approach to Study Anticarcinogenic and Anti-Neuroinflammatory Effects of Curcumin.

Veronika Furlan,Janez Konc,Urban Bren

doi:10.3390/molecules23123351

Veronika Furlan, Janez Konc + Show 1 more

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https://doi.org/10.3390/molecules23123351

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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.

Highlights

With the availability of an ever increasing number of three-dimensional protein structures and the onset of high-performance computing systems, molecular docking provides a fast, low-cost alternative to the experimental screening of large compound libraries [1]
We identified inhibitory effects of curcumin on numerous signaling pathways involved in carcinogenesis and tumor formation
We found that curcumin potentially binds to proteins playing an important role in cognitive impairment associated with Alzheimer’s disease

Summary

Introduction

With the availability of an ever increasing number of three-dimensional protein structures and the onset of high-performance computing systems, molecular docking provides a fast, low-cost alternative to the experimental screening of large compound libraries [1]. Many small molecules are typically docked into a given protein and their binding free energies are estimated with. Theaim calculation of the freeeffort energies is simplified usingnew various assumptions molecules for further development [2]. The calculation of the binding free energies is simplified using and estimated by a value known as “score” given to the docked binding conformations [3]. A small molecule drug may withknown many as other proteins which can conformations. A small molecule drug activity, may interact with many other proteins Impacts on drug’s overall biological efficacy, promiscuity, and side-effects. Targets), cana single have small significant impacts on into drug’s overall of biological activity, enabling efficacy, In inversewhich docking, molecule is docked a collection protein structures promiscuity, andofside-effects Molecules 2018, 23, x the aim to reduce the time and effort required to identify new candidate drug molecules for further estimated with to reduce thebinding time and required to identify candidate drug development [2].the

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