Exploration for novel inhibitors showing back-to-front approach against VEGFR-2 kinase domain (4AG8) employing molecular docking mechanism and molecular dynamics simulations
Abstract Background Angiogenesis is a process of formation of new blood vessels and is an important criteria demonstrated by cancer cells. Over a period of time, these cancer cells infect the other parts of the healthy body by a process called progression. The objective of the present article is to...
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| Format: | Article |
| Language: | English |
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BMC
2018-03-01
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| Series: | BMC Cancer |
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| Online Access: | http://link.springer.com/article/10.1186/s12885-018-4050-1 |
| _version_ | 1818145210157236224 |
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| author | Shailima Rampogu Ayoung Baek Amir Zeb Keun Woo Lee |
| author_facet | Shailima Rampogu Ayoung Baek Amir Zeb Keun Woo Lee |
| author_sort | Shailima Rampogu |
| collection | DOAJ |
| description | Abstract Background Angiogenesis is a process of formation of new blood vessels and is an important criteria demonstrated by cancer cells. Over a period of time, these cancer cells infect the other parts of the healthy body by a process called progression. The objective of the present article is to identify a drug molecule that inhibits angiogenesis and progression. Methods In this pursuit, ligand based pharmacophore virtual screening was employed, generating a pharmacophore model, Hypo1 consisting of four features. Furthermore, this Hypo1 was validated recruiting, Fischer’s randomization, test set method and decoy set method. Later, Hypo1 was allowed to screen databases such as Maybridge, Chembridge, Asinex and NCI and were further filtered by ADMET filters and Lipinski’s Rule of Five. A total of 699 molecules that passed the above criteria, were challenged against 4AG8, an angiogenic drug target employing GOLD v5.2.2. Results The results rendered by molecular docking, DFT and the MD simulations showed only one molecule (Hit) obeyed the back-to-front approach. This molecule displayed a dock score of 89.77, involving the amino acids, Glu885 and Cys919, Asp1046, respectively and additionally formed several important hydrophobic interactions. Furthermore, the identified lead molecule showed interactions with key residues when challenged with CDK2 protein, 1URW. Conclusion The lead candidate showed several interactions with the crucial residues of both the targets. Furthermore, we speculate that the residues Cys919 and Leu83 are important in the development of dual inhibitor. Therefore, the identified lead molecule can act as a potential inhibitor for angiogenesis and progression. |
| first_indexed | 2024-12-11T11:59:50Z |
| format | Article |
| id | doaj.art-6ea673634a9e4e59a0258311b5877444 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-11T11:59:50Z |
| publishDate | 2018-03-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-6ea673634a9e4e59a0258311b58774442022-12-22T01:08:07ZengBMCBMC Cancer1471-24072018-03-0118112110.1186/s12885-018-4050-1Exploration for novel inhibitors showing back-to-front approach against VEGFR-2 kinase domain (4AG8) employing molecular docking mechanism and molecular dynamics simulationsShailima Rampogu0Ayoung Baek1Amir Zeb2Keun Woo Lee3Division of Applied Life Science (BK21 Plus Program), Systems and Synthetic Agrobiotech Center (SSAC), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU)Division of Applied Life Science (BK21 Plus Program), Systems and Synthetic Agrobiotech Center (SSAC), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU)Division of Applied Life Science (BK21 Plus Program), Systems and Synthetic Agrobiotech Center (SSAC), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU)Division of Applied Life Science (BK21 Plus Program), Systems and Synthetic Agrobiotech Center (SSAC), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU)Abstract Background Angiogenesis is a process of formation of new blood vessels and is an important criteria demonstrated by cancer cells. Over a period of time, these cancer cells infect the other parts of the healthy body by a process called progression. The objective of the present article is to identify a drug molecule that inhibits angiogenesis and progression. Methods In this pursuit, ligand based pharmacophore virtual screening was employed, generating a pharmacophore model, Hypo1 consisting of four features. Furthermore, this Hypo1 was validated recruiting, Fischer’s randomization, test set method and decoy set method. Later, Hypo1 was allowed to screen databases such as Maybridge, Chembridge, Asinex and NCI and were further filtered by ADMET filters and Lipinski’s Rule of Five. A total of 699 molecules that passed the above criteria, were challenged against 4AG8, an angiogenic drug target employing GOLD v5.2.2. Results The results rendered by molecular docking, DFT and the MD simulations showed only one molecule (Hit) obeyed the back-to-front approach. This molecule displayed a dock score of 89.77, involving the amino acids, Glu885 and Cys919, Asp1046, respectively and additionally formed several important hydrophobic interactions. Furthermore, the identified lead molecule showed interactions with key residues when challenged with CDK2 protein, 1URW. Conclusion The lead candidate showed several interactions with the crucial residues of both the targets. Furthermore, we speculate that the residues Cys919 and Leu83 are important in the development of dual inhibitor. Therefore, the identified lead molecule can act as a potential inhibitor for angiogenesis and progression.http://link.springer.com/article/10.1186/s12885-018-4050-1AngiogenesisProgressionBack-to-front approachVEGFR-2MD simulations |
| spellingShingle | Shailima Rampogu Ayoung Baek Amir Zeb Keun Woo Lee Exploration for novel inhibitors showing back-to-front approach against VEGFR-2 kinase domain (4AG8) employing molecular docking mechanism and molecular dynamics simulations BMC Cancer Angiogenesis Progression Back-to-front approach VEGFR-2 MD simulations |
| title | Exploration for novel inhibitors showing back-to-front approach against VEGFR-2 kinase domain (4AG8) employing molecular docking mechanism and molecular dynamics simulations |
| title_full | Exploration for novel inhibitors showing back-to-front approach against VEGFR-2 kinase domain (4AG8) employing molecular docking mechanism and molecular dynamics simulations |
| title_fullStr | Exploration for novel inhibitors showing back-to-front approach against VEGFR-2 kinase domain (4AG8) employing molecular docking mechanism and molecular dynamics simulations |
| title_full_unstemmed | Exploration for novel inhibitors showing back-to-front approach against VEGFR-2 kinase domain (4AG8) employing molecular docking mechanism and molecular dynamics simulations |
| title_short | Exploration for novel inhibitors showing back-to-front approach against VEGFR-2 kinase domain (4AG8) employing molecular docking mechanism and molecular dynamics simulations |
| title_sort | exploration for novel inhibitors showing back to front approach against vegfr 2 kinase domain 4ag8 employing molecular docking mechanism and molecular dynamics simulations |
| topic | Angiogenesis Progression Back-to-front approach VEGFR-2 MD simulations |
| url | http://link.springer.com/article/10.1186/s12885-018-4050-1 |
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