Natural Sciences
http://hdl.handle.net/10034/311955
2024-03-28T22:22:19Z
2024-03-28T22:22:19Z
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
Naglah, Ahmed M.
Ullah, Ihsan
Ziedan, Noha
Elhallaoui, Menana
http://hdl.handle.net/10034/628365
2023-12-19T01:49:53Z
2023-12-07T00:00:00Z
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; Naglah, Ahmed M.; Ullah, Ihsan; Ziedan, Noha; Elhallaoui, Menana
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.
2023-12-07T00:00:00Z
Three methods to measure the dissolution activation energy of cellulosic fibres using time-temperature superposition
Liang, Yunhao
Ries, Michael
Hine, Peter
http://hdl.handle.net/10034/628243
2023-11-01T01:42:14Z
2022-04-28T00:00:00Z
Three methods to measure the dissolution activation energy of cellulosic fibres using time-temperature superposition
Liang, Yunhao; Ries, Michael; Hine, Peter
Three methods are established to explore the dissolution kinetics of cellulosic fibres in the ionic liquid 1-ethyl-3-methyl-imidazolium acetate ([C2mim][OAc]), based on optical microscopic images of processed dried cellulose and cellulose hydrogels. The dissolution process for different times at various temperatures was analysed using time-temperature superposition, and from this the dissolution was found to follow an Arrhenius behaviour. Three values for the activation energy of dissolution were obtained from three different quantifying methods; these were found to agree, giving an average value of 73 ± 2 kJ/mol. A new method is developed to determine the swelling ratio of different regions of the processed cellulose samples, along with the different water volume fractions contained therein. The findings will be of interest to researchers making all cellulose composites and those studying the dissolution of cellulose by ionic liquids.
© 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
2022-04-28T00:00:00Z
Pyrolysis activation energy of cellulosic fibres investigated by a method derived from the first order global model
Liang, Yunhao
Hine, Peter
Ries, Michael
http://hdl.handle.net/10034/628242
2023-11-01T01:42:05Z
2022-12-30T00:00:00Z
Pyrolysis activation energy of cellulosic fibres investigated by a method derived from the first order global model
Liang, Yunhao; Hine, Peter; Ries, Michael
The pyrolysis kinetics of cellulosic fibres, a natural cotton yarn (NCY) and a mercerized cotton yarn (MCY), has been explored with a modified first order global analysis method (FOG), via a series of non-isothermal experiments, using thermogravimetric analysis (TGA). The modified FOG analysis routine was developed to overcome discrepancy in heating rate and the difference between exact results and approximations in integrals. The intrinsic pyrolysis activation energy, with temperature range tending to zero, was found to be independent of heating rate and approximation used, giving average values of 153 ± 2 kJ/mol for NCY and 192 ± 7 kJ/mol for MCY. This proves the applicability of the reported analysis routine under the conducted TGA measurements. The reasons for different values were hypothesized to be the difference in chemical composition and crystalline
structure. The findings provide a new approach in the investigation on pyrolysis kinetics of biomass and factors impacting their pyrolytic behaviour.
© 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license
2022-12-30T00:00:00Z
Identification of Disalicyloyl Curcumin as a Potential DNA Polymerase Inhibitor for Marek’s Disease Herpesvirus: A Computational Study Using Virtual Screening and Molecular Dynamics Simulations
Cherif, Aziza
Basharat, Zarrin
Yaseen, Muhammad
Bhat, Mashooq Ahmad
Uddin, Imad
Ziedan, Noha
Mabood, Fazal
Sadfi-Zouaoui, Najla
Messaoudi, Abdelmonaem
http://hdl.handle.net/10034/628087
2023-11-17T15:55:06Z
2023-09-12T00:00:00Z
Identification of Disalicyloyl Curcumin as a Potential DNA Polymerase Inhibitor for Marek’s Disease Herpesvirus: A Computational Study Using Virtual Screening and Molecular Dynamics Simulations
Cherif, Aziza; Basharat, Zarrin; Yaseen, Muhammad; Bhat, Mashooq Ahmad; Uddin, Imad; Ziedan, Noha; Mabood, Fazal; Sadfi-Zouaoui, Najla; Messaoudi, Abdelmonaem
Marek’s disease virus (MDV) is a highly contagious and persistent virus that causes T-lymphoma in chickens, posing a significant threat to the poultry industry despite the availability of vaccines. The emergence of new virulent strains has further intensified the challenge of designing effective antiviral drugs for MDV. In this study, our main objective was to identify novel antiviral phytochemicals through in silico analysis. We employed Alphafold to construct a three-dimensional (3D) structure of the MDV DNA polymerase, a crucial enzyme involved in viral replication. To ensure the accuracy of the structural model, we validated it using tools available at the SAVES server. Subsequently, a diverse dataset containing thousands of compounds, primarily derived from plant sources, was subjected to molecular docking with the MDV DNA polymerase model, utilizing AutoDock software V 4.2. Through comprehensive analysis of the docking results, we identified Disalicyloyl curcumin as a promising drug candidate that exhibited remarkable binding affinity, with a minimum energy of −12.66 Kcal/mol, specifically targeting the DNA polymerase enzyme. To further assess its potential, we performed molecular dynamics simulations, which confirmed the stability of Disalicyloyl curcumin within the MDV system. Experimental validation of its inhibitory activity in vitro can provide substantial support for its effectiveness. The outcomes of our study hold significant implications for the poultry industry, as the discovery of efficient antiviral phytochemicals against MDV could substantially mitigate the economic losses associated with this devastating disease.
2023-09-12T00:00:00Z