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Molecular Docking, DFT and Antiproliferative Properties of 4‐(3,4‐dimethoxyphenyl)−3‐(4‐methoxyphenyl)−1‐phenyl‐1H‐pyrazolo[3,4‐b]pyridine as Potent Anticancer Agent with CDK2 and PIM1 Inhibition Potency
Binjubair, Faizah A. Almansour, Basma S. Ziedan, Noha Abdel‐Aziz, Alaa A.‐M. Al‐Rashood, Sara T. Elgohary, Mohamed K. Elkotamy, Mahmoud S. Abdel‐Aziz, Hatem A.
Binjubair, Faizah A.
Almansour, Basma S.
Ziedan, Noha
Abdel‐Aziz, Alaa A.‐M.
Al‐Rashood, Sara T.
Elgohary, Mohamed K.
Elkotamy, Mahmoud S.
Abdel‐Aziz, Hatem A.
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2024-10-28
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Abstract
Due to the limited effeteness and safety concerns associated with current cancer treatments, there is a pressing need to develop novel therapeutic agents. 4‐(3,4‐Dimethoxyphenyl)−3‐(4‐methoxyphenyl)−1‐phenyl‐1H‐pyrazolo[3,4‐b]pyridine (3) was synthesized and Initially screened on 59 cancer cell lines showed promising anticancer activity, so, it was chosen for a 5‐dose experiment by the NCI/USA. The GI50 values ranged from 1.04 to 8.02 μM on the entire nine panels (57 cell lines), with a GI50 of 2.70 μM for (MG‐MID) panel, indicating an encouraging action. To further explore the molecular attributes of compound 3, we optimized its structure using DFT with the B3LYP/6‐31 + + G(d,p) basis set. We have considered vibrational analysis, bond lengths and angles, FMOs, and MEP for the structure. Additionally, pharmacokinetic assessments were conducted using various in‐silico platforms to evaluate the compound safety. A molecular modeling study created a kinase profile on 44 different kinases. This allowed us to study our compound's binding affinity to these kinases and compare it to the co‐crystallized one. Our findings revealed compound 3 exhibited better binding for half of the tested kinases, suggesting its potential as a multi‐kinase inhibitor. To further validate our computational results, we tested compound 3 for its inhibitory effects on CDK2 and PIM1. Compound 3 exhibited an IC50 of 0.30 µM for CDK2 inhibition, making it five times less active than Roscovitine, which has an IC50 of 0.06 µM. However, compound 3 demonstrated slightly better inhibition of PIM1 compared to Staurosporine. These findings suggest that compound 3 is a promising anticancer agent with the potential for further development into a highly active compound.
Citation
Binjubair, F. A., Almansour, B. S., Ziedan, N. I., Abdel‐Aziz, A. A.‐M., Al‐Rashood, S. T., Elgohary, M. K., Elkotamy, M. S., & Abdel‐Aziz, H. A. (2024). Molecular docking, DFT and antiproliferative properties of 4-(3,4-dimethoxyphenyl)−3-(4-methoxyphenyl)−1-phenyl-1H-pyrazolo[3,4-b]pyridine as potent anticancer agent with CDK2 and PIM1 inhibition potency. Drug Development Research, 85(7), e70009. https://doi.org/10.1002/ddr.70009
Publisher
Wiley
Journal
Drug Development Research
Research Unit
DOI
10.1002/ddr.70009
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PubMed Central ID
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Article
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Description
This is the peer reviewed version of the following article: [Binjubair, F. A., Almansour, B. S., Ziedan, N. I., Abdel‐Aziz, A. A.‐M., Al‐Rashood, S. T., Elgohary, M. K., Elkotamy, M. S., & Abdel‐Aziz, H. A. (2024). Molecular docking, DFT and antiproliferative properties of 4-(3,4-dimethoxyphenyl)−3-(4-methoxyphenyl)−1-phenyl-1H-pyrazolo[3,4-b]pyridine as potent anticancer agent with CDK2 and PIM1 inhibition potency. Drug Development Research, 85(7), e70009], which has been published in final form at [https://doi.org/10.1002/ddr.70009] This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.
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ISSN
0272-4391
EISSN
1098-2299
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Researchers Supporting Project number (RSP-2024/103), King Saud University, Riyadh, Saudi Arabia.