In silico identification of novel CDK4 inhibitors for retinoblastoma
Retinoblastoma is a kind of cancer that mostly affects children's eyes, and this study intends to find drugs that can suppress the protein kinase cyclin-dependent kinase 4 (CDK4). CDK4 overexpression leads to the hyper-phosphorylation of RB tumor suppressor protein, which ultimately results in...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-12-01
|
| Series: | Chemical Physics Impact |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2667022424002871 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850270213605425152 |
|---|---|
| author | Mukesh kumar Vikas Srivastava Uma Devi KhemRaj Nackwal Mohammad Z. Ahmed Prakash K. Shukla |
| author_facet | Mukesh kumar Vikas Srivastava Uma Devi KhemRaj Nackwal Mohammad Z. Ahmed Prakash K. Shukla |
| author_sort | Mukesh kumar |
| collection | DOAJ |
| description | Retinoblastoma is a kind of cancer that mostly affects children's eyes, and this study intends to find drugs that can suppress the protein kinase cyclin-dependent kinase 4 (CDK4). CDK4 overexpression leads to the hyper-phosphorylation of RB tumor suppressor protein, which ultimately results in uncontrolled cell division. Aberration of cell cycle regulation, specifically the excessive expression of transcription factors responsible for uncontrolled cell division causes retinoblastoma progression. Hence, we screened 25,000 kinase-targeted small molecules against CDK-4 by Glide in Maestro, the top 11 were chosen based on docking scores, binding modes, chemical variety, and other parameters. We ran molecular dynamics (MD) simulations of top hits found in the docking studies and determined their free binding energy. This helped us to understand their thermodynamic and dynamic properties, as well as confirm the docking results, finally the two most promising ligands (3396 and 960) were obtained. As a result of our research, we have identified promising new compounds for treating retinoblastoma. To validate the possible therapeutic and preventative effects of this ligand, rigorous experimental validation, animal studies as well as clinical trials would be required. |
| format | Article |
| id | doaj-art-63bbde441ba04f92941f33a8e263ad74 |
| institution | OA Journals |
| issn | 2667-0224 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Chemical Physics Impact |
| spelling | doaj-art-63bbde441ba04f92941f33a8e263ad742025-08-20T01:52:44ZengElsevierChemical Physics Impact2667-02242024-12-01910074310.1016/j.chphi.2024.100743In silico identification of novel CDK4 inhibitors for retinoblastomaMukesh kumar0Vikas Srivastava1Uma Devi2KhemRaj Nackwal3Mohammad Z. Ahmed4Prakash K. Shukla5Department of Biophysics, All India Institute of Medical Sciences, New Delhi, IndiaSMAS, Galgotias University, Greater Noida, Uttar Pradesh, IndiaCentre for Bio-Separation Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, IndiaDepartment of Optometry, CT university, Ludhiana, IndiaDepartment of Pharmacognosy, college of Pharmacy, King Saud University, Riyadh, Saudi ArabiaCentre for Bio-Separation Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India; Corresponding author.Retinoblastoma is a kind of cancer that mostly affects children's eyes, and this study intends to find drugs that can suppress the protein kinase cyclin-dependent kinase 4 (CDK4). CDK4 overexpression leads to the hyper-phosphorylation of RB tumor suppressor protein, which ultimately results in uncontrolled cell division. Aberration of cell cycle regulation, specifically the excessive expression of transcription factors responsible for uncontrolled cell division causes retinoblastoma progression. Hence, we screened 25,000 kinase-targeted small molecules against CDK-4 by Glide in Maestro, the top 11 were chosen based on docking scores, binding modes, chemical variety, and other parameters. We ran molecular dynamics (MD) simulations of top hits found in the docking studies and determined their free binding energy. This helped us to understand their thermodynamic and dynamic properties, as well as confirm the docking results, finally the two most promising ligands (3396 and 960) were obtained. As a result of our research, we have identified promising new compounds for treating retinoblastoma. To validate the possible therapeutic and preventative effects of this ligand, rigorous experimental validation, animal studies as well as clinical trials would be required.http://www.sciencedirect.com/science/article/pii/S2667022424002871CDK4Drug discoveryRetinoblastomaEye researchMolecular dynamicsFree energy |
| spellingShingle | Mukesh kumar Vikas Srivastava Uma Devi KhemRaj Nackwal Mohammad Z. Ahmed Prakash K. Shukla In silico identification of novel CDK4 inhibitors for retinoblastoma Chemical Physics Impact CDK4 Drug discovery Retinoblastoma Eye research Molecular dynamics Free energy |
| title | In silico identification of novel CDK4 inhibitors for retinoblastoma |
| title_full | In silico identification of novel CDK4 inhibitors for retinoblastoma |
| title_fullStr | In silico identification of novel CDK4 inhibitors for retinoblastoma |
| title_full_unstemmed | In silico identification of novel CDK4 inhibitors for retinoblastoma |
| title_short | In silico identification of novel CDK4 inhibitors for retinoblastoma |
| title_sort | in silico identification of novel cdk4 inhibitors for retinoblastoma |
| topic | CDK4 Drug discovery Retinoblastoma Eye research Molecular dynamics Free energy |
| url | http://www.sciencedirect.com/science/article/pii/S2667022424002871 |
| work_keys_str_mv | AT mukeshkumar insilicoidentificationofnovelcdk4inhibitorsforretinoblastoma AT vikassrivastava insilicoidentificationofnovelcdk4inhibitorsforretinoblastoma AT umadevi insilicoidentificationofnovelcdk4inhibitorsforretinoblastoma AT khemrajnackwal insilicoidentificationofnovelcdk4inhibitorsforretinoblastoma AT mohammadzahmed insilicoidentificationofnovelcdk4inhibitorsforretinoblastoma AT prakashkshukla insilicoidentificationofnovelcdk4inhibitorsforretinoblastoma |