Rational computational Design of new-Generation EGFR tyrosine kinase (EGFR-TK) inhibitors
A library of 45 novel compounds, derivatives of 2,3-diphenyl-2,3-dihydro-1H-quinazolin-4-one, were designed as potential EGFR inhibitors. This work describes in-silico study utilizing structure-based drug design (SBDD) and ligand-based drug design (LBDD) methodologies, incorporating Absorption, Dist...
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Elsevier
2025-05-01
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| Series: | Results in Chemistry |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S221171562500222X |
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| author | Chandraprakash Gond Nikhil Kumar Akanksha Mishra Shivani Daksh Anupama Datta Anjani Kumar Tiwari |
| author_facet | Chandraprakash Gond Nikhil Kumar Akanksha Mishra Shivani Daksh Anupama Datta Anjani Kumar Tiwari |
| author_sort | Chandraprakash Gond |
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| description | A library of 45 novel compounds, derivatives of 2,3-diphenyl-2,3-dihydro-1H-quinazolin-4-one, were designed as potential EGFR inhibitors. This work describes in-silico study utilizing structure-based drug design (SBDD) and ligand-based drug design (LBDD) methodologies, incorporating Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) profiling, 3D-QSAR, molecular docking, and molecular dynamics (MD) simulations. ADMET profile of all the compounds were evaluated. A predictive 3D-QSAR model showed R(Alanazi et al., 20162), Rpred2, and Q2 values as 0.95, 0.62, and 0.52, respectively. The designed compounds showed binding affinities ranging from −6.9 to −8.4 kcal/mol when docked against the target protein (PDBID-6LUD). Top inhibitors included compounds 12, 13, 15, 26, 27, 28, 29, 30, 43, and 45 which demonstrated binding affinities more than −8.0 kcal/mol. Out of those, highest docking score was for compound 12 (−8.4 kcal/mol), surpassing the known anticancer drug Vandetanib (−8.0 kcal/mol). In addition, 100 ns MD simulations validated the stability of the protein-ligand complexes, confirming the potential of the selected compounds as potent EGFR inhibitor. |
| format | Article |
| id | doaj-art-15ead91b183949d4b8cae4e73756b1b3 |
| institution | OA Journals |
| issn | 2211-7156 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
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| series | Results in Chemistry |
| spelling | doaj-art-15ead91b183949d4b8cae4e73756b1b32025-08-20T02:09:18ZengElsevierResults in Chemistry2211-71562025-05-011510223910.1016/j.rechem.2025.102239Rational computational Design of new-Generation EGFR tyrosine kinase (EGFR-TK) inhibitorsChandraprakash Gond0Nikhil Kumar1Akanksha Mishra2Shivani Daksh3Anupama Datta4Anjani Kumar Tiwari5Department of Chemistry, Babasaheb Bhimrao Ambedkar University (A Central University), Lucknow 226025, Uttar Pradesh, IndiaInstitute of Nuclear Medicine and Allied Science, DRDO, Delhi 110054, India; Department of Chemistry, Indian Institute of Technology, Delhi 110016, IndiaDepartment of Chemistry, Babasaheb Bhimrao Ambedkar University (A Central University), Lucknow 226025, Uttar Pradesh, IndiaInstitute of Nuclear Medicine and Allied Science, DRDO, Delhi 110054, India; Department of Chemistry, Indian Institute of Technology, Delhi 110016, IndiaInstitute of Nuclear Medicine and Allied Science, DRDO, Delhi 110054, IndiaDepartment of Chemistry, Babasaheb Bhimrao Ambedkar University (A Central University), Lucknow 226025, Uttar Pradesh, India; Corresponding author.A library of 45 novel compounds, derivatives of 2,3-diphenyl-2,3-dihydro-1H-quinazolin-4-one, were designed as potential EGFR inhibitors. This work describes in-silico study utilizing structure-based drug design (SBDD) and ligand-based drug design (LBDD) methodologies, incorporating Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) profiling, 3D-QSAR, molecular docking, and molecular dynamics (MD) simulations. ADMET profile of all the compounds were evaluated. A predictive 3D-QSAR model showed R(Alanazi et al., 20162), Rpred2, and Q2 values as 0.95, 0.62, and 0.52, respectively. The designed compounds showed binding affinities ranging from −6.9 to −8.4 kcal/mol when docked against the target protein (PDBID-6LUD). Top inhibitors included compounds 12, 13, 15, 26, 27, 28, 29, 30, 43, and 45 which demonstrated binding affinities more than −8.0 kcal/mol. Out of those, highest docking score was for compound 12 (−8.4 kcal/mol), surpassing the known anticancer drug Vandetanib (−8.0 kcal/mol). In addition, 100 ns MD simulations validated the stability of the protein-ligand complexes, confirming the potential of the selected compounds as potent EGFR inhibitor.http://www.sciencedirect.com/science/article/pii/S221171562500222XCADDDockingEGFR |
| spellingShingle | Chandraprakash Gond Nikhil Kumar Akanksha Mishra Shivani Daksh Anupama Datta Anjani Kumar Tiwari Rational computational Design of new-Generation EGFR tyrosine kinase (EGFR-TK) inhibitors Results in Chemistry CADD Docking EGFR |
| title | Rational computational Design of new-Generation EGFR tyrosine kinase (EGFR-TK) inhibitors |
| title_full | Rational computational Design of new-Generation EGFR tyrosine kinase (EGFR-TK) inhibitors |
| title_fullStr | Rational computational Design of new-Generation EGFR tyrosine kinase (EGFR-TK) inhibitors |
| title_full_unstemmed | Rational computational Design of new-Generation EGFR tyrosine kinase (EGFR-TK) inhibitors |
| title_short | Rational computational Design of new-Generation EGFR tyrosine kinase (EGFR-TK) inhibitors |
| title_sort | rational computational design of new generation egfr tyrosine kinase egfr tk inhibitors |
| topic | CADD Docking EGFR |
| url | http://www.sciencedirect.com/science/article/pii/S221171562500222X |
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