QSAR, ADMET, molecular docking, and dynamics studies of 1,2,4-triazine-3(2H)-one derivatives as tubulin inhibitors for breast cancer therapy.

Breast cancer remains a leading cause of cancer-related deaths among women globally, necessitating the development of more effective therapeutic agents with minimal side effects. This study explores novel 1,2,4-triazine-3(2H)-one derivatives as potential inhibitors of Tubulin, a pivotal protein in cancer cell division, highlighting a targeted approach in cancer therapy. Using an integrated computational approach, we combined quantitative structure-activity relationship (QSAR) modeling, ADMET profiling, molecular docking, and molecular dynamics simulations to evaluate and predict the efficacy and stability of these compounds. Our QSAR models, developed through rigorous statistical analysis, revealed that descriptors such as absolute electronegativity and water solubility significantly influence inhibitory activity, achieving a predictive accuracy (R2) of 0.849. Molecular docking studies identified compounds with high binding affinities, particularly Pred28, which exhibited the best docking score of - 9.6 kcal/mol. Molecular dynamics simulations conducted over 100 ns provided further insights into the stability of these interactions. Pred28 demonstrated notable stability, with the lowest root mean square deviation (RMSD) of 0.29 nm and root mean square fluctuation (RMSF) values indicative of a tightly bound conformation to Tubulin. The novelty of this work lies in its methodological rigor and the integration of multiple advanced computational techniques to pinpoint compounds with promising therapeutic potential. Our findings advance the current understanding of Tubulin inhibitors and open avenues for the synthesis and experimental validation of these compounds, aiming to offer new solutions for breast cancer treatment.

Multi-combined QSAR, molecular docking, molecular dynamics simulation, and ADMET of Flavonoid derivatives as potent cholinesterase inhibitors.

In searching for a new and efficient therapeutic agent against Alzheimer's disease, a Quantitative structure-activity relationship (QSAR) was derived for 45 Flavonoid derivatives recently synthesized and evaluated as cholinesterase inhibitors. The multiple linear regression method (MLR) was adopted to develop an adequate mathematical model that describes the relationship between a variety of molecular descriptors of the studied compounds and their biological activities (cholinesterase inhibitors). Golbraikh and Tropsha criteria were applied to verify the validity of the built model. The built MLR model was statistically reliable, robust, and predictive (R2 = 0.801, Q2cv = 0.876, R2test = 0.824). Dreiding energy and Molar Refractivity were the major factors that govern the Anti-cholinesterase activity. These results were further exploited to design a new series of Flavonoid derivatives with higher Anti-cholinesterase activities than the existing ones. Thereafter, molecular docking and molecular dynamic studies were performed to predict the binding types of the designed compounds and to investigate their stability at the active site of the Butyrylcholinestérase BuChE protein. The negative and low binding affinity calculated for all designed compounds shows that designed compound 1 has a favorable affinity for the 4TPK. Moreover, molecular dynamics simulation studies confirmed the stability of designed compound 1 in the active pocket of 4TPK over 100 ns. Finally, the ADMET analysis was incorporated to analyze the pharmacokinetics and toxicity parameters. The designed compounds were found to meet the ADMET descriptor criteria at an acceptable level having respectable intestinal permeability and water solubility and can reach the intended destinations.Communicated by Ramaswamy H. Sarma.

In silico design of novel CDK2 inhibitors through QSAR, ADMET, molecular docking and molecular dynamics simulation studies.

The present study aims to investigate about the quantitative structure-activity relationship (QSAR) of a series of Thiazole derivatives reported as anticancer agents (hepatocellular carcinoma), using principally the electronic descriptors calculated by the DFT method and by applying the multiple linear regression method. The developed model showed good statistical parameters (R2 = 0.725, R2adj = 0.653, MSE = 0.060, R2test = 0.827, Q2cv = 0.536). The energy EHOMO orbital, electronic energy (TE), shape coefficient (I), number of rotatable bonds (NROT), and index of refraction (n) were revealed to be the main descriptors influencing the anti-cancer activity. Further, new Thiazole derivatives have been designed and their activities and pharmacokinetic properties have been predicted using the validated QSAR model. The designed molecules were then assessed to molecular docking (MD), and molecular dynamic (MDs) simulation accompanied by the calculation of the binding affinity using MMPBSA script according to 100 ns a simulation trajectory, to study both their affinity and their stability towards CDK2 as a target protein for the cancer disease treatment. This research concluded with the identification of four new CDK2 inhibitors which are A1, A3, A5, and A6 showing good pharmacokinetic properties. The MDs results revealed that the newly designed compound A5 remained stable in the active center of the discovered CDK2 protein, indicating its potential as a novel inhibitor for the treatment of hepatocellular carcinoma. The current findings may eventually contribute to the development of robust CDK2 inhibitors in the future.Communicated by Ramaswamy H. Sarma.

Experimental and Theoretical Tests on the Corrosion Protection of Mild Steel in Hydrochloric Acid Environment by the Use of Pyrazole Derivative.

In this study, 1,5-diallyl-1H-pyrazolo [3,4-d] pyrimidin-4 (5H)-one (PPD) was evaluated as an anticorrosion agent for mild steel (MS) in 1 M HCl. The analysis was performed by weight loss (WL), potentiodynamic polarization measurement, and electrochemical impedance spectroscopy (EIS). The Tafel polarization showed that PPD is a mixed-type inhibitor and reaches 94% of the protective efficiency at 10-3 M. EIS results indicated that the resistance to charge transfer increases with increasing inhibitor concentration and the corrosion of MS is controlled by a charge transfer process. The inhibitor adsorption on the MS surface obeyed the Langmuir's adsorption isotherm. Thermodynamic parameters were calculated to elaborate the corrosion inhibition mechanism. The micrographic analysis revealed the existence of a barrier layer on the electrode surface with the presence of PPD. Theoretical examinations performed by electronic/atomic computer simulations confirmed that the obtained results were found to be consistent with experimental findings.

Chemical reactivities and molecular docking studies of parthenolide with the main protease of HEP-G2 and SARS-CoV-2.

We have used bioinformatics to identify drugs for the treatment of COVID-19, using drugs already being tested for the treatment as benchmarks like Remdesivir and Chloroquine. Our findings provide further support for drugs that are already being explored as therapeutic agents for the treatment of COVID-19 and identify promising new targets that merit further investigation. In addition, the epoxidation of Parthenolide 1 using peracids, has been scrutinized within the MEDT at the B3LYP/6-311(d,p) computational level. DFT results showed a high chemoselectivity on the double bond C3[bond, double bond]C4, in full agreement with the experimental outcomes. ELF analysis demonstrated that epoxidation reaction took place through a one-step mechanism, in which the formation of the two new C-O single bonds is somewhat asynchronous.

MEDT study of the 1,3-DC reaction of diazomethane with Psilostachyin and investigation about the interactions of some pyrazoline derivatives with protease (Mpro) of nCoV-2.

The molecular electronic density theory (MEDT) was invested to elucidate the chemo-, regio- and stereo-selectivity of the 1,3-dipolar cycloaddition between Diazomethane (DZM) and Psilostachyin (PSH). The DFT method at B3LYP/6-31 + G (d,p) level of theory was used. Reactivity indices, transition structures theory, IGM and ELF analysis were employed to reveal the mechanism of the reaction. The addition of DZM to PSH takes place through a one-step mechanism and an asynchronous transition states. Eight possible addition channels of reaction were investigated (addition of C (sp2) to Diazomethane at C4, C5, C6 or C7). The addition of C (sp2) at C5 leading to P1 product is the preferred channel. The addition of ether does not affect the chemo-, regio- and stereo-selectivity of the reaction. Analysis of transfer of charges along the IRC path associated with the P1 product shows a polar character for the studied reaction. We have also used the noncovalent interaction (NCI) which is very helpful to reveal the most favored addition channel of the reaction, by analyzing the weak interactions in different TSs. Finally, we investigate about the potential of inhibition of some pyrazoline compounds against COVID-19-Mpro by performing a molecular docking calculations.