Preliminary hypothetical assessment and in silico molecular docking of statin to VEGFR2 and VEGFR3 protein complex associated with angiogenesis and lymphangiogenesis in diabetic wounds

Divya Pamu; Selvaraj Ayyamperumal; Munikumar Manne; Vyshnavi Tallapaneni; Chandrasekar Joghee Nanjan Moola; Veera Venkata Satyanarayana Reddy Karri

doi:10.7324/JAPS.2023.118396

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Abstract

Vascular endothelial growth factor (VEGF) receptors are the critical drivers for blood vessel formation and lymphangiogenesis in diabetic wounds. However, due to the high blood glucose levels, advanced glycation end products release inflammatory mediators, which lead to hypoxic conditions that decrease the synthesis of essential growth factors and degeneration of the blood vessels necessary for the recovery of the diabetic wound. Hence, repurposing statins and identifying the binding potential to the active amino acid residues on the vascular endothelial growth factor receptor (VEGFR 2) and VEGFR 3 receptor could be a preliminary analysis and hypothetical computational challenge that statins can bind to VEGFs. That initiates the VEGF levels and reduces the inflammation associated with the conversion of M2 macrophages. Hence VEGFR 2 and VEGFR 3 are promising therapeutic targets for starting angiogenesis and lymphangiogenesis in diabetic wounds. Furthermore, the statins (Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin, and Simvastatin) subjected to computational molecular docking (Lib docking), and the best statins are selected based on the LibDock score and hydrogen and hydrophobic bond interactions. The results revealed that Atorvastatin (125.90 and 126.0), Fluvastatin (126.37 and 120.0), Pravastatin (129.90 and 128.6), and Rosuvastatin (130.01 and 130.62 ) had shown a significant binding potential to VEGFR2 and VEGFR3 protein complex and more excellent LibDock score with less variation when compared with the remaining statin molecules. Furthermore, the selected molecules were subjected to computational pharmacophore modeling and toxicity studies. The pharmacophore modeling was carried out to identify the feature set amino acids between the ligand and protein complex, followed by hypothetical confirmation of toxicity when the statin molecules interact with the skin tissue to determine carcinogenicity and skin sensitivity. The toxicity studies revealed that the four statins molecules showed moderate to less skin sensitivity and non-carcinogenicity. In addition, they have demonstrated different solubility parameters computationally. The preliminary hypothetical analysis can be a computational proof for further targeting statins (Atorvastatin, Fluvastatin, Pravastatin, and Rosuvastatin) to VEGFR2 and VEGFR3 for promoting angiogenesis and lymphangiogenesis in diabetic wounds. Taking these evidence-based docking results could provide a future pathway to carry out further research characterization and evaluation of statins for treating and managing diabetic wounds.

Citation:

Pamu D, Ayyamperumal S, Manne M, Tallapaneni V, Moola CJN, Karri VVSNR. Preliminary hypothetical assessment and in silico molecular docking of statin to VEGFR2 and VEGFR3 protein complex associated with angiogenesis and lymphangiogenesis in diabetic wounds. J Appl Pharm Sci, 2023; 13(Suppl 1):009–020. https://doi.org/10.7324/JAPS.2023.118396

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Aldana PC, Khachemoune A. Diabetic foot ulcers: appraising standard of care and reviewing new trends in management. Am J Clin Dermatol, 2020; 21(2):255-64. https://doi.org/10.1007/s40257-019-00495-x
Asai J, Takenaka H, Hirakawa S, Sakabe JI, Hagura A, Kishimoto S, Maruyama K, Kajiya K, Kinoshita S, Tokura Y, Katoh N. Topical simvastatin accelerates wound healing in diabetes by enhancing angiogenesis and lymphangiogenesis. Am J Pathol, 2012; 181(6):2217-24. https://doi.org/10.1016/j.ajpath.2012.08.023
Benest AV, Harper SJ, Herttuala SY, Alitalo K, Bates DO. VEGF-C induced angiogenesis preferentially occurs at a distance from lymphangiogenesis. Cardiovasc Res, 2008; 78(2):315-23. https://doi.org/10.1093/cvr/cvm094
Cui L, Liang J, Liu H, Zhang K, Li J. Nanomaterials for angiogenesis in skin tissue engineering. Tissue Eng Part B Rev, 2020; 26(3):203-16. https://doi.org/10.1089/ten.teb.2019.0337
Fong CW. Statins in therapy: understanding their hydrophilicity, lipophilicity, binding to 3-hydroxy-3-methylglutaryl-CoA reductase, ability to cross the blood brain barrier and metabolic stability based on electrostatic molecular orbital studies. Eur J Med Chem, 2014; 85:661-74. https://doi.org/10.1016/j.ejmech.2014.08.037
Furuhashi A, Rakhmatia YD, Ayukawa Y, Koyano K. Titanium membrane layered between fluvastatin-loaded poly (lactic-co-glycolic) acid for guided bone regeneration. Regen Biomater, 2022; 9:11. https://doi.org/10.1093/rb/rbac061
Gulcan E, Gulcan A, Erbilen E, Toker S. Statins may be useful in diabetic foot ulceration treatment and prevention. Med Hypotheses, 2007; 69(6):1313-5. https://doi.org/10.1016/j.mehy.2007.03.022
Hadrian K, Willenborg S, Bock F, Cursiefen C, Eming SA, Hos D. Macrophage-mediated tissue vascularization: similarities and differences between cornea and skin. Front Immunol, 2021; 12:667830. https://doi.org/10.3389/fimmu.2021.667830
Jere SW, Houreld NN, Abrahamse H. Role of the PI3K/AKT (mTOR and GSK3β) signalling pathway and photobiomodulation in diabetic wound healing. Cytokine Growth Factor Rev, 2019; 50:52-9. https://doi.org/10.1016/j.cytogfr.2019.03.001
Jussila L, Alitalo K. Vascular growth factors and lymphangiogenesis. Physiol Rev, 2002; 82(3):673-700. https://doi.org/10.1152/physrev.00005.2002
Kisko K, Brozzo MS, Missimer J, Schleier T, Menzel A, Leppänen VM, Alitalo K, Walzthoeni T, Aebersold R, Ballmer-Hofer K. Structural analysis of vascular endothelial growth factor receptor-2/ligand complexes by small-angle X-ray solution scattering. FASEB J, 2011; 25(9):2980-6. https://doi.org/10.1096/fj.11-185397
Ko HH, Lareu RR, Dix BR, Hughes JD. In vitro antibacterial effects of statins against bacterial pathogens causing skin infections. Eur J Clin Microbiol Infect Dis, 2018; 37(6):1125-35. https://doi.org/10.1007/s10096-018-3227-5
Laing T, Hanson R, Chan F, Bouchier-Hayes D. Effect of pravastatin on experimental diabetic wound healing. J Surg Res, 2010; 161(2):336-40. https://doi.org/10.1016/j.jss.2009.01.024
Leppänen VM, Tvorogov D, Kisko K, Prota AE, Jeltsch M, Anisimov A, Markovic-Mueller S, Stuttfeld E, Goldie KN, Ballmer-Hofer K, Alitalo K. Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation. Proc Nat Acad Sci, 2013; 110(32):12960-5. https://doi.org/10.1073/pnas.1301415110
Melincovici CS, Bo?ca AB, ?u?man S, M?rginean M, Mihu C, Istrate M, Moldovan IM, Roman AL, Mihu CM. Vascular endothelial growth factor (VEGF)-key factor in normal and pathological angiogenesis. Rom J Morphol Embryol, 2018; 59(2):455-67.
Mollahosseini A, Saadati S, Abdelrasoul A. Effects of mussel-inspired co-deposition of 2-hydroxymethyl methacrylate and poly (2-methoxyethyl acrylate) on the hydrophilicity and binding tendency of common hemodialysis membranes: molecular dynamics simulations and molecular docking studies. J Comput Chem, 2022; 43(1):57-73. https://doi.org/10.1002/jcc.26773
Nosrati H, Aramideh Khouy R, Nosrati A, Khodaei M, Banitalebi-Dehkordi M, Ashrafi-Dehkordi K, Sanami S, Alizadeh Z. Nanocomposite scaffolds for accelerating chronic wound healing by enhancing angiogenesis. J Nanobiotechnol, 2021a; 19(1):1-21. https://doi.org/10.1186/s12951-020-00755-7
Nosrati H, Khodaei M, Alizadeh Z, Banitalebi-Dehkordi M. Cationic, anionic and neutral polysaccharides for skin tissue engineering and wound healing applications. Int J Biol Macromol, 2021b; 192:298-322. https://doi.org/10.1016/j.ijbiomac.2021.10.013
Pal S, Kumar V, Kundu B, Bhattacharya D, Preethy N, Reddy MP, Talukdar A. Ligand-based pharmacophore modeling, virtual screening and molecular docking studies for discovery of potential topoisomerase I inhibitors. Comput Struct Biotechnol J, 2019; 17:291-310. https://doi.org/10.1016/j.csbj.2019.02.006
Piaggesi A, Apelqvist J. (eds.). The diabetic foot syndrome. Karger Medical and Scientific Publishers, Switzerland, 2017. https://doi.org/10.1159/isbn.978-3-318-06145-1
Potenza MA, Gagliardi S, Nacci C, Carratu MR, Montagnani M. Endothelial dysfunction in diabetes: from mechanisms to therapeutic targets. Curr Med Chem, 2009; 16(1):94-112. https://doi.org/10.2174/092986709787002853
Sangande F, Julianti E, Tjahjono DH. Ligand-based pharmacophore modeling, molecular docking, and molecular dynamic studies of dual tyrosine kinase inhibitor of EGFR and VEGFR2. Int J Mol Sci, 2020; 21(20):7779. https://doi.org/10.3390/ijms21207779
Tejaswini T, Keerthana M, Vidyavathi M, Kumar RV. Design and evaluation of atorvastatin-loaded chitosan-hydroxyapatite composite bioscaffolds for wound-healing activity. Future J Pharm Sci, 2020; 6(1):1-4. https://doi.org/10.1186/s43094-020-00125-y
Tessier N, Moawad F, Amri N, Brambilla D, Martel C. Focus on the lymphatic route to optimize drug delivery in cardiovascular medicine. Pharmaceutics, 2021; 13(8):1200. https://doi.org/10.3390/pharmaceutics13081200
Toker S, Gulcan E, Cayc? MK, Olgun EG, Erbilen E, Özay Y. Topical atorvastatin in the treatment of diabetic wounds. Am J Med Sci, 2009; 338(3):201-4. https://doi.org/10.1097/MAJ.0b013e3181aaf209
Vanommeslaeghe K, MacKerell Jr AD. CHARMM additive and polarizable force fields for biophysics and computer-aided drug design. Biochim Biophys Acta (BBA)-Gen Subj, 2015; 1850(5):861-71. https://doi.org/10.1016/j.bbagen.2014.08.004
Wang X. Metalloproteinases in the development of hypertension and cardiac remodeling. University of Alberta, Edmonton, Canada, 2013.
Wang K, Li B, Xie Y, Xia N, Li M, Gao G. Statin rosuvastatin inhibits apoptosis of human coronary artery endothelial cells through upregulation of the JAK2/STAT3 signaling pathway. Mol Med Rep, 2020; 22(3):2052-62. https://doi.org/10.3892/mmr.2020.11266
Yang Y, Xie P, Opatowsky Y, Schlessinger J. Direct contacts between extracellular membrane-proximal domains are required for VEGF receptor activation and cell signaling. Proc Nat Acad Sci, 2010; 107(5):1906-11. https://doi.org/10.1073/pnas.0914052107
Yasunami N, Ayukawa Y, Furuhashi A, Atsuta I, Rakhmatia YD, Moriyama Y, Masuzaki T, Koyano K. Acceleration of hard and soft tissue healing in the oral cavity by a single transmucosal injection of fluvastatin-impregnated poly (lactic-co-glycolic acid) microspheres. An in vitro and rodent in vivo study. Biomed Mater, 2015; 11(1):015001. https://doi.org/10.1088/1748-6041/11/1/015001
Yele V, Saha N, Md AA. Possible role of rivoglitazone thiazolidine class of drug as dual-target therapeutic agent for bacterial infections: an in silico study. Med Hypotheses, 2019; 131:109305. https://doi.org/10.1016/j.mehy.2019.109305
Zaki RM, Seshadri VD, Mutayran AS, Elsawaf LA, Hamad AM, Almurshedi AS, Yusif RM, Said M. Wound healing efficacy of rosuvastatin transethosomal gel, I optimal optimization, histological and in vivo evaluation. Pharmaceutics, 2022; 14(11):2521. https://doi.org/10.3390/pharmaceutics14112521
Zhang Y, Li Q, Youn JY, Cai H. Protein phosphotyrosine phosphatase 1B (PTP1B) in calpain-dependent feedback regulation of vascular endothelial growth factor receptor (VEGFR2) in endothelial cells: implications in VEGF-dependent angiogenesis and diabetic wound healing. J Biol Chem, 2017; 292(2):407-16. https://doi.org/10.1074/jbc.M116.766832

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Akershoek JJ, Brouwer KM, Vlig M, Boekema BK, Beelen RH, Middelkoop E, Ulrich MM. Differential effects of losartan and atorvastatin in partial and full thickness burn wounds. PloS one, 2017; 12(6):e0179350. https://doi.org/10.1371/journal.pone.0179350

Aldana PC, Khachemoune A. Diabetic foot ulcers: appraising standard of care and reviewing new trends in management. Am J Clin Dermatol, 2020; 21(2):255-64. https://doi.org/10.1007/s40257-019-00495-x

Asai J, Takenaka H, Hirakawa S, Sakabe JI, Hagura A, Kishimoto S, Maruyama K, Kajiya K, Kinoshita S, Tokura Y, Katoh N. Topical simvastatin accelerates wound healing in diabetes by enhancing angiogenesis and lymphangiogenesis. Am J Pathol, 2012; 181(6):2217-24. https://doi.org/10.1016/j.ajpath.2012.08.023

Benest AV, Harper SJ, Herttuala SY, Alitalo K, Bates DO. VEGF-C induced angiogenesis preferentially occurs at a distance from lymphangiogenesis. Cardiovasc Res, 2008; 78(2):315-23. https://doi.org/10.1093/cvr/cvm094

Cui L, Liang J, Liu H, Zhang K, Li J. Nanomaterials for angiogenesis in skin tissue engineering. Tissue Eng Part B Rev, 2020; 26(3):203-16. https://doi.org/10.1089/ten.teb.2019.0337

Fong CW. Statins in therapy: understanding their hydrophilicity, lipophilicity, binding to 3-hydroxy-3-methylglutaryl-CoA reductase, ability to cross the blood brain barrier and metabolic stability based on electrostatic molecular orbital studies. Eur J Med Chem, 2014; 85:661-74. https://doi.org/10.1016/j.ejmech.2014.08.037

Furuhashi A, Rakhmatia YD, Ayukawa Y, Koyano K. Titanium membrane layered between fluvastatin-loaded poly (lactic-co-glycolic) acid for guided bone regeneration. Regen Biomater, 2022; 9:11. https://doi.org/10.1093/rb/rbac061

Gulcan E, Gulcan A, Erbilen E, Toker S. Statins may be useful in diabetic foot ulceration treatment and prevention. Med Hypotheses, 2007; 69(6):1313-5. https://doi.org/10.1016/j.mehy.2007.03.022

Hadrian K, Willenborg S, Bock F, Cursiefen C, Eming SA, Hos D. Macrophage-mediated tissue vascularization: similarities and differences between cornea and skin. Front Immunol, 2021; 12:667830. https://doi.org/10.3389/fimmu.2021.667830

Jere SW, Houreld NN, Abrahamse H. Role of the PI3K/AKT (mTOR and GSK3β) signalling pathway and photobiomodulation in diabetic wound healing. Cytokine Growth Factor Rev, 2019; 50:52-9. https://doi.org/10.1016/j.cytogfr.2019.03.001

Jussila L, Alitalo K. Vascular growth factors and lymphangiogenesis. Physiol Rev, 2002; 82(3):673-700. https://doi.org/10.1152/physrev.00005.2002

Kisko K, Brozzo MS, Missimer J, Schleier T, Menzel A, Leppänen VM, Alitalo K, Walzthoeni T, Aebersold R, Ballmer-Hofer K. Structural analysis of vascular endothelial growth factor receptor-2/ligand complexes by small-angle X-ray solution scattering. FASEB J, 2011; 25(9):2980-6. https://doi.org/10.1096/fj.11-185397

Ko HH, Lareu RR, Dix BR, Hughes JD. In vitro antibacterial effects of statins against bacterial pathogens causing skin infections. Eur J Clin Microbiol Infect Dis, 2018; 37(6):1125-35. https://doi.org/10.1007/s10096-018-3227-5

Laing T, Hanson R, Chan F, Bouchier-Hayes D. Effect of pravastatin on experimental diabetic wound healing. J Surg Res, 2010; 161(2):336-40. https://doi.org/10.1016/j.jss.2009.01.024

Leppänen VM, Tvorogov D, Kisko K, Prota AE, Jeltsch M, Anisimov A, Markovic-Mueller S, Stuttfeld E, Goldie KN, Ballmer-Hofer K, Alitalo K. Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation. Proc Nat Acad Sci, 2013; 110(32):12960-5. https://doi.org/10.1073/pnas.1301415110

Melincovici CS, Bo?ca AB, ?u?man S, M?rginean M, Mihu C, Istrate M, Moldovan IM, Roman AL, Mihu CM. Vascular endothelial growth factor (VEGF)-key factor in normal and pathological angiogenesis. Rom J Morphol Embryol, 2018; 59(2):455-67.

Mollahosseini A, Saadati S, Abdelrasoul A. Effects of mussel-inspired co-deposition of 2-hydroxymethyl methacrylate and poly (2-methoxyethyl acrylate) on the hydrophilicity and binding tendency of common hemodialysis membranes: molecular dynamics simulations and molecular docking studies. J Comput Chem, 2022; 43(1):57-73. https://doi.org/10.1002/jcc.26773

Nosrati H, Aramideh Khouy R, Nosrati A, Khodaei M, Banitalebi-Dehkordi M, Ashrafi-Dehkordi K, Sanami S, Alizadeh Z. Nanocomposite scaffolds for accelerating chronic wound healing by enhancing angiogenesis. J Nanobiotechnol, 2021a; 19(1):1-21. https://doi.org/10.1186/s12951-020-00755-7

Nosrati H, Khodaei M, Alizadeh Z, Banitalebi-Dehkordi M. Cationic, anionic and neutral polysaccharides for skin tissue engineering and wound healing applications. Int J Biol Macromol, 2021b; 192:298-322. https://doi.org/10.1016/j.ijbiomac.2021.10.013

Pal S, Kumar V, Kundu B, Bhattacharya D, Preethy N, Reddy MP, Talukdar A. Ligand-based pharmacophore modeling, virtual screening and molecular docking studies for discovery of potential topoisomerase I inhibitors. Comput Struct Biotechnol J, 2019; 17:291-310. https://doi.org/10.1016/j.csbj.2019.02.006

Piaggesi A, Apelqvist J. (eds.). The diabetic foot syndrome. Karger Medical and Scientific Publishers, Switzerland, 2017. https://doi.org/10.1159/isbn.978-3-318-06145-1

Potenza MA, Gagliardi S, Nacci C, Carratu MR, Montagnani M. Endothelial dysfunction in diabetes: from mechanisms to therapeutic targets. Curr Med Chem, 2009; 16(1):94-112. https://doi.org/10.2174/092986709787002853

Sangande F, Julianti E, Tjahjono DH. Ligand-based pharmacophore modeling, molecular docking, and molecular dynamic studies of dual tyrosine kinase inhibitor of EGFR and VEGFR2. Int J Mol Sci, 2020; 21(20):7779. https://doi.org/10.3390/ijms21207779

Tejaswini T, Keerthana M, Vidyavathi M, Kumar RV. Design and evaluation of atorvastatin-loaded chitosan-hydroxyapatite composite bioscaffolds for wound-healing activity. Future J Pharm Sci, 2020; 6(1):1-4. https://doi.org/10.1186/s43094-020-00125-y

Tessier N, Moawad F, Amri N, Brambilla D, Martel C. Focus on the lymphatic route to optimize drug delivery in cardiovascular medicine. Pharmaceutics, 2021; 13(8):1200. https://doi.org/10.3390/pharmaceutics13081200

Toker S, Gulcan E, Cayc? MK, Olgun EG, Erbilen E, Özay Y. Topical atorvastatin in the treatment of diabetic wounds. Am J Med Sci, 2009; 338(3):201-4. https://doi.org/10.1097/MAJ.0b013e3181aaf209

Vanommeslaeghe K, MacKerell Jr AD. CHARMM additive and polarizable force fields for biophysics and computer-aided drug design. Biochim Biophys Acta (BBA)-Gen Subj, 2015; 1850(5):861-71. https://doi.org/10.1016/j.bbagen.2014.08.004

Wang X. Metalloproteinases in the development of hypertension and cardiac remodeling. University of Alberta, Edmonton, Canada, 2013.

Wang K, Li B, Xie Y, Xia N, Li M, Gao G. Statin rosuvastatin inhibits apoptosis of human coronary artery endothelial cells through upregulation of the JAK2/STAT3 signaling pathway. Mol Med Rep, 2020; 22(3):2052-62. https://doi.org/10.3892/mmr.2020.11266

Yang Y, Xie P, Opatowsky Y, Schlessinger J. Direct contacts between extracellular membrane-proximal domains are required for VEGF receptor activation and cell signaling. Proc Nat Acad Sci, 2010; 107(5):1906-11. https://doi.org/10.1073/pnas.0914052107

Yasunami N, Ayukawa Y, Furuhashi A, Atsuta I, Rakhmatia YD, Moriyama Y, Masuzaki T, Koyano K. Acceleration of hard and soft tissue healing in the oral cavity by a single transmucosal injection of fluvastatin-impregnated poly (lactic-co-glycolic acid) microspheres. An in vitro and rodent in vivo study. Biomed Mater, 2015; 11(1):015001. https://doi.org/10.1088/1748-6041/11/1/015001

Yele V, Saha N, Md AA. Possible role of rivoglitazone thiazolidine class of drug as dual-target therapeutic agent for bacterial infections: an in silico study. Med Hypotheses, 2019; 131:109305. https://doi.org/10.1016/j.mehy.2019.109305

Zaki RM, Seshadri VD, Mutayran AS, Elsawaf LA, Hamad AM, Almurshedi AS, Yusif RM, Said M. Wound healing efficacy of rosuvastatin transethosomal gel, I optimal optimization, histological and in vivo evaluation. Pharmaceutics, 2022; 14(11):2521. https://doi.org/10.3390/pharmaceutics14112521

Zhang Y, Li Q, Youn JY, Cai H. Protein phosphotyrosine phosphatase 1B (PTP1B) in calpain-dependent feedback regulation of vascular endothelial growth factor receptor (VEGFR2) in endothelial cells: implications in VEGF-dependent angiogenesis and diabetic wound healing. J Biol Chem, 2017; 292(2):407-16. https://doi.org/10.1074/jbc.M116.766832