Calculation of binding affinity of JAK1 inhibitors via accurately computational estimation

Le, Thi-Thuy-Huong; Tran, Linh; Nguyen, Minh Tam; Pham, Minh Quan; Phung, Huong Thi Thu

doi:10.1080/07391102.2022.2118830

Cited by 3 publications

(1 citation statement)

References 62 publications

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“…The manner of inhibitor binding in JAK1 was remarkably similar to that observed in JAK2, emphasizing the difficulties in designing JAK-specific inhibitors that target the ATP-binding site ( Williams et al, 2009 ; Virtanen et al, 2023 ). Nonetheless, variations in the ATP-binding sites of JAK1 and JAK2 were observed, providing a foundation for the rational design of JAK2- and JAK1-specific inhibitors ( Le et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

Revealing innovative JAK1 and JAK3 inhibitors: a comprehensive study utilizing QSAR, 3D-Pharmacophore screening, molecular docking, molecular dynamics, and MM/GBSA analyses

Faris,

Cacciatore,

Alnajjar

et al. 2024

Front. Mol. Biosci.

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The heterocycle compounds, with their diverse functionalities, are particularly effective in inhibiting Janus kinases (JAKs). Therefore, it is crucial to identify the correlation between their complex structures and biological activities for the development of new drugs for the treatment of rheumatoid arthritis (RA) and cancer. In this study, a diverse set of 28 heterocyclic compounds selective for JAK1 and JAK3 was employed to construct quantitative structure-activity relationship (QSAR) models using multiple linear regression (MLR). Artificial neural network (ANN) models were employed in the development of QSAR models. The robustness and stability of the models were assessed through internal and external methodologies, including the domain of applicability (DoA). The molecular descriptors incorporated into the model exhibited a satisfactory correlation with the receptor-ligand complex structures of JAKs observed in X-ray crystallography, making the model interpretable and predictive. Furthermore, pharmacophore models ADRRR and ADHRR were designed for each JAK1 and JAK3, proving effective in discriminating between active compounds and decoys. Both models demonstrated good performance in identifying new compounds, with an ROC of 0.83 for the ADRRR model and an ROC of 0.75 for the ADHRR model. Using a pharmacophore model, the most promising compounds were selected based on their strong affinity compared to the most active compounds in the studied series each JAK1 and JAK3. Notably, the pharmacokinetic, physicochemical properties, and biological activities of the selected compounds (As compounds ZINC79189223 and ZINC66252348) were found to be consistent with their therapeutic effects in RA, owing to their non-toxic, cholinergic nature, absence of P-glycoprotein, high gastrointestinal absorption, and ability to penetrate the blood-brain barrier. Furthermore, ADMET properties were assessed, and molecular dynamics and MM/GBSA analysis revealed stability in these molecules.

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Section: Introductionmentioning

confidence: 99%

Revealing innovative JAK1 and JAK3 inhibitors: a comprehensive study utilizing QSAR, 3D-Pharmacophore screening, molecular docking, molecular dynamics, and MM/GBSA analyses

Faris,

Cacciatore,

Alnajjar

et al. 2024

Front. Mol. Biosci.

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Novel trans -caffeate hydrazide derivatives: synthesis, inhibition of nitric oxide (NO) production and molecular docking studies

Thuy,

Thuy Linh,

Nguyen Thi Thu

et al. 2023

Natural Product Research

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Potential inhibitory activities of phytoconstituents in Salvia miltiorrhiza against coronary heart disease drug targets using docking and ADMET studies

Man,

Nguyen,

Pham

et al. 2024

Vietnam J. Sci. Technol.

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Coronary heart disease (CHD) is one of the leading causes of death worldwide. The effectiveness of the current drugs is still restricted due to high side effects; thus, it is urgently needed to discover novel compounds for drug development. In the field of drug discovery research, the main target receptors for chemotherapy are identified as ACE, PPAR-γ, HMGR, COX-2, and thrombin. In this study, docking simulations were performed for phytoconstituents of Salvia miltiorrhiza Bunge in searching for compounds with potential inhibitory activities against these proteins. As a result, six compounds were suggested as potential multitarget inhibitors and could be considered for further drug development studies based on docking conformation and ADMET property analysis.

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Calculation of binding affinity of JAK1 inhibitors via accurately computational estimation

Cited by 3 publications

References 62 publications

Revealing innovative JAK1 and JAK3 inhibitors: a comprehensive study utilizing QSAR, 3D-Pharmacophore screening, molecular docking, molecular dynamics, and MM/GBSA analyses

Revealing innovative JAK1 and JAK3 inhibitors: a comprehensive study utilizing QSAR, 3D-Pharmacophore screening, molecular docking, molecular dynamics, and MM/GBSA analyses

Novel trans -caffeate hydrazide derivatives: synthesis, inhibition of nitric oxide (NO) production and molecular docking studies

Potential inhibitory activities of phytoconstituents in Salvia miltiorrhiza against coronary heart disease drug targets using docking and ADMET studies

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