Abstract
Angiogenesis is the growth of new capillaries from existing blood vessels that supply oxygen and nutrients and provide gateways for immune surveillance. Abnormal vessel growth in term of excessive angiogenesis is a hallmark of cancer, inflammatory and eye diseases. VEGFR-2 (vascular endothelial growth factor receptor 2) dominating the process of angiogenesis has led to approval of therapeutic inhibitors and is becoming a promising target for anti-angiogenic drugs. Notwithstanding these successes, the clinical use of current VEGFR-2 blockers is more challenging than anticipated. Taking axitinib as a reference drug, in our study we found three potent VEGFR-2 inhibitors (ZINC08254217, ZINC08254138, and ZINC03838680) from natural derivatives. Each of the three inhibitors acquired a better grid score than axitinib (−62.11) when docked to VEGFR-2. Molecular dynamics simulations demonstrated that ZINC08254217– and ZINC08254138–VEGFR-2 complexes were more stable than axitinib. Similar to bind free energy for axitinib (−54.68 kcal/mol), such for ZINC03838680, ZINC08254217, and ZINC08254138 was −49.37, −43.32, and −32.73 kcal/mol respectively. These results suggested these three compounds could be candidate drugs against angiogenesis, with comparable VEGFR-2 binding affinity of axitinib. Hence findings in our study are able to provide valuable information on discovery of effective anti-angiogenesis therapy.
Highlights
Angiogenesis is the growth of new capillaries from existing blood vessels, which plays a central role during ontogenetic development and is essential in various physiological processes within human body like tissue growth and repair [1]
The subtle difference was that axitinib was redocked to VEGF receptors (VEGFRs)-2 forming three hydrogen bonds with Glu917, Cys919 and Asp1046, while one more hydrogen bond with Glu885 was observed in the 4AG8 structure
These results indicated DOCK could successfully redock the co-crystallized axitinib back into VEGFR-2 with high accuracy
Summary
Angiogenesis is the growth of new capillaries from existing blood vessels, which plays a central role during ontogenetic development and is essential in various physiological processes within human body like tissue growth and repair [1]. Molecular docking-based virtual screening, using a target which is a protein with experimentally determined structure, has become an established method for lead discovery in various drug development projects by filtering large virtual libraries [15,16]. Complementary to virtual screening and molecular docking, molecular dynamics simulation has become a standard tool for understanding the physical basis of interactions between macromolecular (like protein) receptors and their small-molecule ligands in drug discovery [17]. Considering currently available medicines’ limitations, the development of small-molecule inhibitors that prevent the VEGFRs signaling is an attractive anti-angiogenic strategy, since the resulting inhibition is likely less toxic for long-term use than antibody therapeutics [21]. For the sake of potent anti-angiogenesis treatment, we aim at discovering potential VEGFR-2 inhibitors from natural products using computer-aided approaches. We first downloaded structural information of natural derivatives from ZINC [22]; Second, we filtered these molecules via virtual screening; Third, we scored the screening results by molecular docking to find candidate drugs; Lastly, we assessed potential drugs through molecular dynamics simulations
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