Molecular simulation studies to reveal the binding mechanisms of shikonin derivatives inhibiting VEGFR-2 kinase |
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| Institution: | 1. Department of Anatomy, Dongguk University College of Medicine, Gyeongju, 38066, Republic of Korea;2. Department of Biotechnology and Genetic Engineering, Faculty of Biological Sciences, Islamic University, Kushtia, 7003, Bangladesh;3. Department of Pharmacy, University of Science & Technology, Chittagong, 4202, Bangladesh;4. Department of Pharmacy, BGC Trust University Bangladesh, Chittagong, 4381, Bangladesh;5. Department of Pharmacy, Southern University Bangladesh, Chittagong, 4000, Bangladesh;6. Pancreatic Research Group, South Western Sydney Clinical School, University of New South Wales, and Ingham Institute for Applied Medical Research, Liverpool, NSW, 2170, Australia;1. Molecular Bio-Computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa;2. Department of Veterinary Parasitology and Entomology, Faculty of Veterinary Medicine, University of Ibadan, Nigeria;1. V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, 02094, Kyiv-94, Murmanska Str,1, Kyiv, Ukraine;2. Nizhyn Mykola Gogol State University, 16600, Grafska Str. 2, Nizhyn, Chernihivska Oblast, Ukraine;3. P.L. Shupyk National Medical Academy of Postgraduate Education, 04112, Dorogozhytska Str, 9, Kyiv, Ukraine;1. Department of Chemistry, Faculty of Physics and Chemistry, Alzahra University, Tehran, Iran;2. Chemistry Department, Ferdowsi University of Mashhad, Mashhad, Iran;1. Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China;2. Jiangsu Provincial Key Laboratory for Plant Ex Situ Conservation, Institute of Botany, Jiangsu Province and Chinese Academy of Sciences, Nanjing 210014, China |
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| Abstract: | Traditional vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitors can manage angiogenesis; however, severe toxicity and resistance limit their long-term applications in clinical therapy. Shikonin (SHK) and its derivatives could be promising to inhibit the VEGFR-2 mediated angiogenesis, as they are reported to bind in the catalytic kinase domain with low affinity. However, the detailed molecular insights and binding dynamics of these natural inhibitors are unknown, which is crucial for potential SHK based lead design. Therefore, the present study employed molecular modeling and simulations techniques to get insight into the binding behaviors of SHK and its two derivates, β-hydroxyisovalerylshikonin (β-HIVS) and acetylshikonin (ACS). Here the intermolecular interactions between protein and ligands were studied by induced fit docking approach, which were further evaluated by treating QM/MM (quantum mechanics/molecular mechanics) and molecular dynamics (MD) simulation. The result showed that the naphthazarin ring of the SHK derivates is vital for strong binding to the catalytic domain; however, the binding stability can be modulated by the side chain modification. Because of having electrostatic potential, this ring makes essential interactions with the DFG (Asp1046 and Phe1047) motif and also allows interacting with the allosteric binding site. Taken together, the studies will advance our knowledge and scope for the development of new selective VEGFR-2 inhibitors based on SHK and its analogs. |
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| Keywords: | VEGFR-2 Angiogenesis Shikonin derivatives Molecular simulation Induced-fit docking |
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