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.

Autor: Binjubair FA; Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia., Almansour BS; Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia., Ziedan NI; Department of physical, mathematical and Engineering science, Faculty of science, Business and Enterprise, University of Chester, Chester, UK., Abdel-Aziz AA; Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia., Al-Rashood ST; Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia., Elgohary MK; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian-Russian University, Badr City, 11829, Cairo, Egypt., Elkotamy MS; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian-Russian University, Badr City, 11829, Cairo, Egypt., Abdel-Aziz HA; Applied Organic Chemistry Department, National Research Center, Dokki, 12622, Cairo, Egypt.; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University in Alexandria; Canal El Mahmoudia St., Alexandria, 21648, Egypt.
Jazyk: angličtina
Zdroj: Drug development research [Drug Dev Res] 2024 Nov; Vol. 85 (7), pp. e70009.
DOI: 10.1002/ddr.70009
Abstrakt: 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 GI 50 values ranged from 1.04 to 8.02 μM on the entire nine panels (57 cell lines), with a GI 50 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 IC 50 of 0.30 µM for CDK2 inhibition, making it five times less active than Roscovitine, which has an IC 50 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.
(© 2024 Wiley Periodicals LLC.)
Databáze: MEDLINE
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