INVESTIGATION OF THE ACTIVITY OF 8- METHYLQUINOLONES AGAINST MYCOBACTERIUM TUBERCULOSIS USING THEORETICAL MOLECULAR DESCRIPTORS: A CASE STUDY

A quantitative structure-activity relationship (QSAR) study on a set of 36 structurally-similar 8-methylquinolones was performed using a large pool of theoretical molecular descriptors. The molecular structures of the compounds were pre-optimized using molecular mechanics (MM2). Full optimization was done with the density functional theory (DFT) using Becke’s three-parameter hybrid functional with LYP correlation functional in combination with the standard pople’s basis set 6311G*. HOMO and LUMO energies, dipole moment, total energy and many other properties served as quantum-chemical descriptors. The GA-MLRA technique was used to select the most significant descriptors and to generate a linear model for predicting the biological activity, Minimal Inhibitory Concentration (MIC), treated as negative decade logarithm, (pMIC). The best model was obtained with R2=0.90323 . The model was tested internally using the leave-one-out (LOO) cross validation procedure on the training set and validated against the external validation set (Q2 LOO = 0.83115 and R2 Pred = 0.78708 ). The Y-scrambling/randomization validation also confirmed the statistical significance of the model. Leverage approach was used to define the applicability domain of the model. This validated model could be used to design new potential drug candidates, within the 8-methylquinolone family, with high activity against tuberculosis

Molecular Docking and In-silico Pharmacokinetic Investigations towards Designing Multi-target Potent Dengue Virus Inhibitors with enhanced Pharmacokinetic Profile

AbstractThe widespread of dengue infection globally has become a great source of concern especially to developing countries with limited resources to control the spread of the dengue virus vector as such infection characterized by fever, joint pain, etc. may progress to a fatal phase such as dengue hemorrhagic fever and organ failure or dengue shock syndrome. An in-silico method using the DFT approach was employed for the geometric optimisation of phthalazinone derivatives with previously established interaction with NS2B-NS3 protease of dengue virus. Herein, molecular docking was employed to evaluate their biochemical interactions with dengue virus serotype 2 protease NS-5 as multi-target. Likewise, the ADME/PK property of the studied compounds was investigated. The molecular docking calculation showed that the previously reported compound 21 with the best potency against NS2B-NS3 protease had the best docking score of -9.0 kcal/mol against NS-5 protease. The physicochemical and ADME/PK properties result revealed that these compounds are orally bioavailable with high gastrointestinal absorption, and are all inhibitors of CYP-3A4 and CYP-2D6 except compound 7 which is a non-inhibitor of CYP-2D6. Also, all the compounds are substrates of P-glycoprotein. The information derived from this study can be utilized in the drug discovery process to improve the anti-dengue activity of the studied compounds. This study would provide physicochemical and pharmacokinetics properties required for the identification of potent anti-dengue drugs and other relevant information in drug discovery

QSAR MODELLING OF SOME ANTICANCER PGI50 ACTIVITY ON HL-60 CELL LINES

QSAR (2D and 3D) studies were performed on a series of CAMPTOTHECIN derivatives using Material Studio software (accelrys). QSAR study performed on 102 analogues of which 90 were used in the training set and the rest 22 considered for the test set.  QSAR study performed using Genetic function approximation (GFA). GFA method came out with good correlation coefficient 0.837 , cross-validated coefficient 0.792  and R2Test of 0.9408. A highly predictive and statistically significant model was generated. The QSAR models were found to accurately predict the anticancer activity of structurally diverse test set compounds and to yield reliable clues for further optimization of the of CAMPTOTHECIN derivatives in the data set

Association between insulin-induced weight change and CVD mortality: Evidence from a historic cohort study of 18,814 patients in UK primary care.

BACKGROUND: This study explores the association of insulin-induced weight (wt) gain on cardiovascular outcomes and mortality among patients with type 2 diabetes (T2D) following insulin initiation using real-world data. METHODS: A historical cohort study was performed in 18,814 adults with insulin-treated T2D derived from the UK The Health Improvement Network database. Based on the average weight change of 5 kg, 1 year postinsulin initiation, patients were grouped into 5 categories (>5 kg wt loss; 1.0-5.0 kg wt loss; no wt change; 1.0-5.0 kg wt gain; >5.0 kg wt gain) and followed-up for 5 years. Cox proportional hazard models and Kaplan-Meier estimators were fitted to estimate the hazards of a 3-point composite of nonfatal myocardial infarction, stroke, and all-cause mortality between categories. RESULTS: The median age was 62.8 (IQR: 52.3-71.8) years, HbA1c : 8.6% (IQR: 7.4-9.8) and mean BMI: 31.8 (6.5) kg/m2 . The 5 year probability of survival differed significantly within the wt-change categories (log-rank test P value = .0005). Only 1963 composite events occurred. Compared with the weight-neutral group, the risk of composite events was 31% greater in the >5 kg wt-loss group (aHR: 1.31; 95% CI: 1.02, 1.68), the same in the 1.0 to 5.0 kg wt-gain category, but nonsignificantly increased in the 1.0 to 5.0 kg wt loss (15%) and >5.0 kg wt gain (13%) categories, respectively. In the obese subgroup, this risk was 50% (aHR: 1.50, 95% CI: 1.08-2.08) more in the >5 kg weight-loss group compared with the weight-neutral group. CONCLUSION: Insulin-induced weight gain did not translate to adverse cardiovascular outcomes and mortality in patients with T2D. These data provide reassurance on the cardiovascular safety of insulin patients with T2D

Mechanism of Water Absorption Behaviour in Groundnut Shell Powder Filled Waste HDPE Composites

Communication in Physical Sciences, 2020, 6(1): 793-802 Authors: Joseph Jacob and Paul Andrew P. Mamza Received 22 November 2020/Accepted 02 December 2020 The mechanism of water absorption and its effect on mechanical properties of groundnut shell powder (GSP) reinforced waste high density polyethylene (wHDPE) was studied at different temperatures. The composite samples were developed via melt mixing and compression moulding techniques respectively. The percentage weight fraction of reinforcement was varied (0, 5, 10, 15, 20 and 25 %). The initial rate of water absorption and the maximum were observed to increase for all GSP filled wHDPE composites samples as the weight fraction of reinforcement increases. The maximum moisture uptake at room temperature was 4.77 % after 720 hours of exposure compared to 6.74 % moisture uptake at elevated temperature showing a 6.73 % increase for 25 % GSP-wHDPE composites. This indicates that sorption at room temperature takes longer time to reach equilibrium than sorption at elevated temperatures. The effects of moisture absorption and temperature on several performance parameters such as tensile strength, flexural strength, hardness value and impact strength revealed a decrease in these properties after 720 hours of immersion in distilled water at 27This indicates that long term exposure of GSP-wHDPE composites in water affects the interfacial adhesion between the polymer matrix and the fibre, creates de-bonding, leading to decrease in mechanical propertie

Quantitative structure–activity relationship study on potent anticancer compounds against MOLT-4 and P388 leukemia cell lines

A quantitative structure–activity relationship (QSAR) study was carried out on 112 anticancer compounds to develop a robust model for the prediction of anti-leukemia activity (pGI50) against MOLT-4 and P388 leukemia cell lines. The Genetic algorithm (GA) and multiple linear regression analysis (MLRA) were used to select the descriptors and to generate the correlation models that relate the structural features to the biological activities. The final equations consist of 15 and 10 molecular descriptors calculated using the paDEL molecular descriptor software. The GA-MLRA analysis showed that the Conventional bond order ID number of order 1 (piPC1), number of atomic composition (nAtomic), and Largest absolute eigenvalue of Burden modified matrix – n 7/weighted by relative mass (SpMax7_Bhm) play a significant role in predicting the anticancer activities of these compounds. The best QSAR model for MOLT-4 was obtained with R2 value of 0.902, Q2LOO = 0.881 and R2pred = 0.635, while for P388 cell line R2 = 0.904, Q2LOO = 0.856 and R2pred = 0.670. The Y-scrambling/randomization validation also confirms the statistical significance of the models. These models are expected to be useful for predicting the inhibitory activity (pGI50) against MOLT-4 and P388 leukemia cell lines

Effect of Isoberlina Wood Fillers on the Mechanical and Thermal Properties of PVC Composites

Communication in Physical Sciences 2020, 6(1): 706-713 Received 27 August 2020/Accepted 24 September 2020 Mechanical and thermal properties of Isoberlina (IS) wood reinforced polyvinyl chloride composites have been studied. The IS fibre was treated with sodium hydroxide solution to boast the adhesion between the hydrophilic natural fibre and the hydrophobic plastic matrix. The percentage fibre loading was varied from 0, 4, 8, 12, 16, 20 to 24. Dynamic Mechanical Analysis (DMA) technique was used to investigate the effect of Isoberlina wood powder on the thermal properties of polyvinyl chloride (PVC). The mechanical properties: ultimate tensile strength (UTS), elastic modulus and hardness showed an extensive improvement compared to the unreinforced PVC. DMA results showed that composite with 12 wt % IS have higher glass transition temperature and better stiffness stability at elevated temperature than the unreinforced PVC. Isoberlina wood powder can thus serve as a valuable reinforcement in the development of polymer composites

2D-QSAR, Docking, Molecular dynamics simulations with the MM/GBSA approaches against Grave's disease and PTPN22

Graves' disease (GD) is an autoimmune condition that frequently causes hyperthyroidism and thyrotoxicosis. Protein tyrosine phosphatase, non-receptor type 22 (lymphoid) isoform 1 (PTPN22), is a promising therapeutic candidate for treating Graves' disease, rheumatoid arthritis, type 1 diabetes, and other autoimmune disorders. In this dataset, 31 molecular compounds and two standard drugs were optimized using the semi-empirical PM7 theory method via MOPAC v22.0.4 to reveal the key influencing factors contributing to their grave's disease inhibition activity and selectivity. Using QSARIN software, the acquired properties/descriptors were used to create a quantitative structural activities relationship (QSAR) model, and the similarities between the observed and predicted pIC50 values were examined. A molecular docking simulation study also uncovers non-covalent interactions between the investigated compounds and the receptors. The observed ligand-protein interactions with grave's disease proteins (PDB ID: 2XPG and 4QT5) and protein tyrosine phosphatase, non-receptor type 22 (lymphoid) isoform 1 (PTPN22) (PDB ID: 3BRH) were investigated. The pharmacokinetics (ADMET) properties were also investigated. Finally, molecular dynamics (MD) simulation and MMGBSA studies that demonstrated stable trajectory and molecular properties with a consistent interaction profile were used to validate the stability of the compounds in the complex with PTPN22

Dynamic Mechanical Properties and Surface Morphology of Glass/Jute/Kevlar Fibres reinforced Hybrid Composite

Communication in Physical Sciences, 2021, 7(4): 438-443 Authors: Elijah  Danladi*, Paul.A.P. Mamza, S.A. Yaro, M.T. Isa, E. R. Sadiku and S.S. Ray Received: 18 November 2021/Accepted 08 December 2021 The strength and application of polymers can significantly be affected by their mechanical properties, which indicates that measures aimed at altering their mechanical properties will also affect their strength and possible applications The purpose of this study is to investigate the dynamic mechanical properties of the glass/jute /Kevlar hybrid fibres reinforced polypropylene using dynamic mechanical analysis, (DMA) to establish the interfacial bond in relation to storage modulus, loss modulus and damping factor. The samples were prepared using Carver Press at a temperature of 190 oC and a pressure of 500 psi using 1 mm thin films of polypropylene. The results obtained showed that the hybrid composites have a poor interfacial bond which led to molecular motion as the temperature was increasing. The loss modulus was also high, likewise the damping factor. The Scanning Electron Microscope (SEM) micrograms also supported these findings by showing the delamination on impacted samples. These make the hybrid composite a good material for rigid body armor application