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QSAR-driven screening uncovers and designs novel pyrimidine-4,6-diamine derivatives as potent JAK3 inhibitors
Faris, Abdelmoujoud Ibrahim, Ibrahim M. Alnajjar, Radwan Hadni, Hanine Bhat, Mashooq Ahmad Yaseen, Muhammad Chakraborty, Souvik Alsakhen, Nada Shamkh, Israa M. Mabood, Fazal
Faris, Abdelmoujoud
Ibrahim, Ibrahim M.
Alnajjar, Radwan
Hadni, Hanine
Bhat, Mashooq Ahmad
Yaseen, Muhammad
Chakraborty, Souvik
Alsakhen, Nada
Shamkh, Israa M.
Mabood, Fazal
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Other Contributors
EPub Date
Publication Date
2023-12-07
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Abstract
This study presents a robust and integrated methodology that harnesses a range of computational techniques to facilitate the design and prediction of new inhibitors targeting the JAK3/STAT pathway. This methodology encompasses several strategies, including QSAR analysis, pharmacophore modeling, ADMET prediction, covalent docking, molecular dynamics (MD) simulations, and the calculation of binding free energies (MM/GBSA). An efficacious QSAR model was meticulously crafted through the employment of multiple linear regression (MLR). The initial MLR model underwent further refinement employing an artificial neural network (ANN) methodology aimed at minimizing predictive errors. Notably, both MLR and ANN exhibited commendable performance, showcasing R2 values of 0.89 and 0.95, respectively. The model's precision was assessed via leave-one-out cross-validation (CV) yielding a Q2 value of 0.65, supplemented by rigorous Y-randomization. , The pharmacophore model effectively differentiated between active and inactive drugs, identifying potential JAK3 inhibitors, and demonstrated validity with an ROC value of 0.86. The newly discovered and designed inhibitors exhibited high inhibitory potency, ranging from 6 to 8, as accurately predicted by the QSAR models. Comparative analysis with FDA-approved Tofacitinib revealed that the new compounds exhibited promising ADMET properties and strong covalent docking (CovDock) interactions. The stability of the new discovered and designed inhibitors within the JAK3 binding site was confirmed through 500 ns MD simulations, while MM/GBSA calculations supported their binding affinity. Additionally, a retrosynthetic study was conducted to facilitate the synthesis of these potential JAK3/STAT inhibitors. The overall integrated approach demonstrates the feasibility of designing novel JAK3/STAT inhibitors with robust efficacy and excellent ADMET characteristics that surpass Tofacitinib by a significant margin.
Citation
Faris, A., Ibrahim, I. M., Alnajjar, R., Hadni, H., Bhat, M. A., Yaseen, M., Chakraborty, S., Alsakhen, N., Shamkh, I. M., Mabood, F., Naglah, A. M., Ullah, I., Ziedan, N., & Elhallaoui, M. (2025). QSAR-driven screening uncovers and designs novel pyrimidine-4,6-diamine derivatives as potent JAK3 inhibitors. Journal of Biomolecular Structure and Dynamics, 43(2), 757-786. https://doi.org/10.1080/07391102.2023.2283168
Publisher
Taylor & Francis
Journal
Journal of Biomolecular Structure and Dynamics
Research Unit
DOI
10.1080/07391102.2023.2283168
PubMed ID
PubMed Central ID
Type
Article
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Description
Series/Report no.
ISSN
0739-1102
EISSN
1538-0254