Reveal the interaction mechanism of five old drugs targeting VEGFR2 through computational simulations
Graphical abstract
We investigated interactions between five old drugs and VEGFR2 by two molecular docking methods, molecular dynamics simulation and ONIOM-based simulation.
Introduction
Cancer-related deaths are on the rise globally, with an estimated annual increase of 19.3 million cancer cases by 2025 [1]. The variety of cancers and the complex pathogenesis require continuous development of effective and precise drugs. Pharmacologist and Nobel laureate James Black once said, ‘the most fruitful basis for the discovery of a new drug is to start with an old drug’ [2]. The pharmacokinetics and toxicity of the existing old drugs are known, which can greatly reduce the time and money-cost of drug development [3]. According to this superb and attractive strategy, some old drugs have been approved and in clinical test for cancer treatment, including aspirin in colorectal cancer [4], ribavirin in acute myeloid leukemia and breast cancer [5], and nelfinavir in recurrent adenoid cystic cancer of the head and neck (See https://clinicaltrials.gov/) and so on. How do we find new indications for these old drugs? Signature matching, molecular docking, genome-wide association studies, pathway or network mapping and the other data-driven computational approaches are common but effective methods [6].
VEGFR2, vascular endothelial growth factor receptor 2, is a kind of tyrosine kinase. It mediates the signal transduction pathway regulated by vascular endothelial cells, then stimulates the proliferation of vascular endothelial cells, leading to vascular growth. Studies have shown that it is highly expressed in ovarian cancer, thyroid cancer, melanoma and other malignant tumors [7]. The extracellular ligand VEGF binds to VEGFR2, thereby to induce the formation of a homologous dimer complex of VEGFR2, and to change its intracellular domain conformation. These conformational changes cause auto phosphorylation of the tyrosine residue of VEGFR2 and signal downstream, such as Ras, Raf, MAPK, PI3K and Akt [8]. Thus, it is a promising way to find new anticancer drugs targeting VEGFR2.
So far, a variety of small molecule inhibitors targeting VEGFR2 has been developed. According to whether the inhibitors target the ATP-binding site, they are divided into two or three kinds [9]. Small molecules that target the DFG-in conformation of VEGFR2 are called type-І inhibitors, while ligands targeting the DFG-out conformation of VEGFR2 are termed type-II inhibitors or allosteric kinase inhibitors [10,11]. Sorafenib (Bay 43–9006, Bayer), tivozanib (KRN-951, Kirin) and vatalanib (PTK 787, Novartis) are classical type-II VEGFR2 inhibitors [12]. Nowadays, the small molecule inhibitors against VEGFR2 are more or less toxic, which causes fatigue, hypertension, nausea, vomiting, hand-foot skin reaction and weight loss [13], for instance, sorafenib can cause skin toxicity, digestive tract reaction, liver function damage, vascular system toxicity and systemic reaction [14]. Therefore, it is imperative to find new anti-angiogenesis inhibitors with more effectiveness but less side effects.
In this work, our attempt was to elucidate the detailed mechanism of new potential VEGFR2 inhibitors obtained from FDA-approved drugs using computational approaches. We used two different docking methods to obtain potential anti-angiogenic drugs from Drugbank [15], then utilized molecular dynamics (MD) simulations and quantum-chemical calculations to explore the interaction mechanism of these old drugs targeting VEGFR2.
Section snippets
Ligand preparation
The ligands were downloaded from Drugbank [15], which contains the 3D structures of FDA-approved drugs. There were 2337 approved small molecule drugs in it until July 2018 (https://www.drugbank.ca/stats). We removed the drugs that are too flexible to display the certain 3D structures, and that involve a mixture of structures as well. We then obtained 1964 FDA-approved drugs. Finally, these candidate molecules were converted to PDBQT files by software OpenBabel [16] and Raccoon [17].
Molecular docking
AutoDock
Results
Five Old Drugs Exhibited Stable Binding Affinities with VEGFR2 through Two Different Molecular Docking Methods. We first performed re-dock for sorafenib with VEGFR2 to ensure if the present two docking methods are effective for the studied system or not. We showed that similarity was 0.92, Vina score was −11.00 kcal∙mol−1, and total score of Sybyl was 9.03 (Table 1), along with its docking conformation and crystal conformation (Fig. S1), proving that Vina and Sybyl were able to properly
Discussion
In this work, the five obtained compounds (antrafenine No.96, iloperidone No.856, pranlukast No.1401, vilazodone No.1778 and zafirlukast No.1795) were potential VEGFR2 inhibitors. Therein, three compounds have been reported to exhibit potential anti-tumor effects. Our work provided a theoretical methodology for exploring the possible anti-tumor targets of the compounds, then further evidence for their interaction mechanism with VEGFR2.
The binding abilities of five old drugs with VEGFR2 were
Conclusions
We explore the interaction mechanism of five old drugs, iloperidone, vilazodone, pranlukast, zafirlukast, and antrafenine, targeting VEGFR2 from the library of FDA-approved drugs by molecular dockings, MD simulations and ONIOM-based calculations. The receptor-ligand complexes are stable during the interaction process mainly due to the important contribution of Glu-885, Cys-919 and Asp-1046; meanwhile, the changes of hydrogen bond occupancy points out that Lys-868 and Phe-1047 may be a key
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (No. 31571782 and 31771975) and the Natural Science Foundation of Chongqing CSTC (No. cstc2018jcyjAX0765).
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