Reveal the interaction mechanism of five old drugs targeting VEGFR2 through computational simulations

Highlights

• We explore the mechanism of five FDA-approved drugs inhibiting VEGFR2.

• Five drugs exhibit more stable interactions than sorafenib with VEGFR2.

• Zafirlukast presentes the most stable binding affinity with VEGFR2.

• Five old drugs inhibit VEGFR2 by interacting with Cys919, Glu885 and Asp1046.

Abstract

VEGFR2, vascular endothelial growth factor receptor 2, plays an important role in anti-angiogenesis and is an effective target for inhibiting tumor cell proliferation and metastasis. Many small molecule inhibitors have so far exhibited fine therapeutic effects but do not rule out some adverse reactions. From the perspective of the new use of old drugs, we use a combination of two different docking methods, molecular dynamics simulations and quantum-chemical calculations to acquire potential anti-angiogenesis inhibitors from the library of FDA-approved drugs. We attain five FDA-approved old drugs from Drugbank as potential inhibitors against VEGFR2. Therein, the anti-tumor effects of three compounds, including vilazodone (psychiatric drug), pranlukast and zafirlukast (asthma drugs), have been reported by previous experiments but no anti-tumor data is available for the other two compounds, including antrafenine (analgesic and anti-inflammatory drug) and iloperidone (psychiatric drug). These five compounds exhibit more stable interaction than sorafenib as a market-oriented drug targeting VEGFR2. In parallel, there is a most stable interaction for zafirlukast while a weakest interaction for iloperidone with VEGFR2. We show that these five compounds bind with the hydrophobic cavity of VEGFR2, then forming hydrogen bond interactions with three key residues, Glu-885, Cys-919 and Asp-1046. Lys-868 and Phe-1047 play an important role in stabilizing the interaction conformation. The binding poses of pranlukast and vilazodone are similar to that of sorafenib, whereas antrafenine and zafirlukast act differently from sorafenib, focusing on the direction difference of the respective ring structure. This work may help to develop new and effective anti-angiogenic inhibitors.

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.