Elucidating the therapeutic potential of indazole derivative bindarit against K-ras receptor: An in-silico analysis using molecular dynamics exploration
Ras gene is frequently mutated in cancer. Among different subtypes of Ras gene, K-Ras mutation occurs in nearly 30 % of human cancers. K-Ras mutation, specifically K-Ras (G12D) mutation is prevalent in cancers like lung, colon and pancreatic cancer. During cancer occurrence, mutant Ras remain in act...
Saved in:
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-03-01
|
| Series: | Biochemistry and Biophysics Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405580824002772 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850074794523885568 |
|---|---|
| author | Parmar Keshri Nandan Jayanthi Sivaraman |
| author_facet | Parmar Keshri Nandan Jayanthi Sivaraman |
| author_sort | Parmar Keshri Nandan |
| collection | DOAJ |
| description | Ras gene is frequently mutated in cancer. Among different subtypes of Ras gene, K-Ras mutation occurs in nearly 30 % of human cancers. K-Ras mutation, specifically K-Ras (G12D) mutation is prevalent in cancers like lung, colon and pancreatic cancer. During cancer occurrence, mutant Ras remain in activated form (GTP bound state) for cancer cell proliferation. In the quest for a potential K-Ras inhibitor, nitrogen-containing indazole derivatives can show promise as inhibitors, as they have numerous therapeutic properties like anti-inflammatory, anti-viral and anti-tumor. Furthermore, among various indazole derivatives, “Bindarit” is an important therapeutic compound which could have potential inhibitory action against K-Ras due to its structural resemblance with reference compound “Benzimidazole”. So, the current study is an attempt to find out the inhibitory effect of Bindarit against K-Ras activation by binding to a pocket which is adjacent to the switch I/II regions of the K-Ras receptor. AutoDock tool was used to investigate the binding affinity of protein ligand interaction and GROMACS package was utilised to assess their interactions in a dynamic setting. Bindarit shows better binding affinity than reference with binding energy of −7.3 kcal/mol. Upon ligand binding conformational changes take place, which could lead to the loss of GTPase activity. Consequently, further downstream signalling of the K-Ras pathway would be blocked and this could lead to the inhibition of K-Ras dependent cancer cell proliferation. However, further validation of present study can be done through experimental assay such as cytotoxic and protein expression analysis. |
| format | Article |
| id | doaj-art-0d3bfd0fc0f34d8dab311f90366aef3c |
| institution | DOAJ |
| issn | 2405-5808 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biochemistry and Biophysics Reports |
| spelling | doaj-art-0d3bfd0fc0f34d8dab311f90366aef3c2025-08-20T02:46:29ZengElsevierBiochemistry and Biophysics Reports2405-58082025-03-014110191310.1016/j.bbrep.2024.101913Elucidating the therapeutic potential of indazole derivative bindarit against K-ras receptor: An in-silico analysis using molecular dynamics explorationParmar Keshri Nandan0Jayanthi Sivaraman1School of Biosciences and Technology, Vellore Institute of Technology, Vellore, IndiaCorresponding author.; School of Biosciences and Technology, Vellore Institute of Technology, Vellore, IndiaRas gene is frequently mutated in cancer. Among different subtypes of Ras gene, K-Ras mutation occurs in nearly 30 % of human cancers. K-Ras mutation, specifically K-Ras (G12D) mutation is prevalent in cancers like lung, colon and pancreatic cancer. During cancer occurrence, mutant Ras remain in activated form (GTP bound state) for cancer cell proliferation. In the quest for a potential K-Ras inhibitor, nitrogen-containing indazole derivatives can show promise as inhibitors, as they have numerous therapeutic properties like anti-inflammatory, anti-viral and anti-tumor. Furthermore, among various indazole derivatives, “Bindarit” is an important therapeutic compound which could have potential inhibitory action against K-Ras due to its structural resemblance with reference compound “Benzimidazole”. So, the current study is an attempt to find out the inhibitory effect of Bindarit against K-Ras activation by binding to a pocket which is adjacent to the switch I/II regions of the K-Ras receptor. AutoDock tool was used to investigate the binding affinity of protein ligand interaction and GROMACS package was utilised to assess their interactions in a dynamic setting. Bindarit shows better binding affinity than reference with binding energy of −7.3 kcal/mol. Upon ligand binding conformational changes take place, which could lead to the loss of GTPase activity. Consequently, further downstream signalling of the K-Ras pathway would be blocked and this could lead to the inhibition of K-Ras dependent cancer cell proliferation. However, further validation of present study can be done through experimental assay such as cytotoxic and protein expression analysis.http://www.sciencedirect.com/science/article/pii/S2405580824002772BioavailabilityGTPaseCancerIndazoleProliferation |
| spellingShingle | Parmar Keshri Nandan Jayanthi Sivaraman Elucidating the therapeutic potential of indazole derivative bindarit against K-ras receptor: An in-silico analysis using molecular dynamics exploration Biochemistry and Biophysics Reports Bioavailability GTPase Cancer Indazole Proliferation |
| title | Elucidating the therapeutic potential of indazole derivative bindarit against K-ras receptor: An in-silico analysis using molecular dynamics exploration |
| title_full | Elucidating the therapeutic potential of indazole derivative bindarit against K-ras receptor: An in-silico analysis using molecular dynamics exploration |
| title_fullStr | Elucidating the therapeutic potential of indazole derivative bindarit against K-ras receptor: An in-silico analysis using molecular dynamics exploration |
| title_full_unstemmed | Elucidating the therapeutic potential of indazole derivative bindarit against K-ras receptor: An in-silico analysis using molecular dynamics exploration |
| title_short | Elucidating the therapeutic potential of indazole derivative bindarit against K-ras receptor: An in-silico analysis using molecular dynamics exploration |
| title_sort | elucidating the therapeutic potential of indazole derivative bindarit against k ras receptor an in silico analysis using molecular dynamics exploration |
| topic | Bioavailability GTPase Cancer Indazole Proliferation |
| url | http://www.sciencedirect.com/science/article/pii/S2405580824002772 |
| work_keys_str_mv | AT parmarkeshrinandan elucidatingthetherapeuticpotentialofindazolederivativebindaritagainstkrasreceptoraninsilicoanalysisusingmoleculardynamicsexploration AT jayanthisivaraman elucidatingthetherapeuticpotentialofindazolederivativebindaritagainstkrasreceptoraninsilicoanalysisusingmoleculardynamicsexploration |