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.

Effect of Peganum harmala Total Alkaloid Extract on Sexual Behavior and Sperm Parameters in Male Mice.

The study was designed to evaluate the effects of the total alkaloid extract of Algerian Peganum harmala seeds on sexual behavior and male reproductive function. After two weeks of acclimatization, the male mice were randomly divided into four groups (seven mice in each group). For 35 days, the extract was administered orally at dose levels of 6.25, 12.5, and 25 mg/kg body weight per day to the respective groups of male mice (n = 7) and normal saline daily to the control group. On day 28, sexual behavior parameters were recorded. At the end of the trial, reproductive organ weights, sperm quality, seminal fructose, and testosterone hormone levels were evaluated. The three treated groups were compared with the control using statistical variance analysis (one-way ANOVA, p < 0.05), followed by Tukey's test. The results of the groups treated with 12.5 and 6.25 mg/kg of P. harmala alkaloid revealed the MF and IF parameters to be the lowest compared to the control group (p < 0.05). However, the male mice treated with 25 mg/kg recorded the highest values. A low significant value of ML was observed in the group treated with 25 mg/kg of the total alkaloid extract of P. harmala compared to the control group (p < 0.01), while a rise was observed in the concentration group treated with 6.25 mg/kg. Regarding IL, the male mice treated with different concentrations of the total alkaloid extract of P. harmala recorded a higher time than the control group. Moreover, an increase in the gonadosomatic index was noticed in all groups compared to the control group. However, there was a significant (p < 0.01) decrease in the sperm counts of the groups treated with 12.5 mg/kg and 6.25 mg/kg. However, there was no significant difference in the motility, membrane integrity, and total antioxidant capacity of sperm cells compared to the control. The extract treatment also brought about a non-significant increase in fructose content of the seminal vesicle and serum testosterone level. The findings of this study demonstrate that the extract acts in a dose-dependent manner, and it has varying effects on the reproductive parameters of male mice.

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.

Towards designing of a potential new HIV-1 protease inhibitor using QSAR study in combination with Molecular docking and Molecular dynamics simulations.

Human Immunodeficiency Virus type 1 protease (HIV-1 PR) is one of the most challenging targets of antiretroviral therapy used in the treatment of AIDS-infected people. The performance of protease inhibitors (PIs) is limited by the development of protease mutations that can promote resistance to the treatment. The current study was carried out using statistics and bioinformatics tools. A series of thirty-three compounds with known enzymatic inhibitory activities against HIV-1 protease was used in this paper to build a mathematical model relating the structure to the biological activity. These compounds were designed by software; their descriptors were computed using various tools, such as Gaussian, Chem3D, ChemSketch and MarvinSketch. Computational methods generated the best model based on its statistical parameters. The model's applicability domain (AD) was elaborated. Furthermore, one compound has been proposed as efficient against HIV-1 protease with comparable biological activity to the existing ones; this drug candidate was evaluated using ADMET properties and Lipinski's rule. Molecular Docking performed on Wild Type, and Mutant Type HIV-1 proteases allowed the investigation of the interaction types displayed between the proteases and the ligands, Darunavir (DRV) and the new drug (ND). Molecular dynamics simulation was also used in order to investigate the complexes' stability allowing a comparative study on the performance of both ligands (DRV & ND). Our study suggested that the new molecule showed comparable results to that of darunavir and maybe used for further experimental studies. Our study may also be used as pipeline to search and design new potential inhibitors of HIV-1 proteases.

The exo- or endonucleolytic preference of bovine pancreatic ribonuclease A depends on its subsites structure and on the substrate size.

The cleavage pattern of oligocytidylic acid substrates by bovine pancreatic ribonuclease A (RNase A) was studied by means of reversed-phase HPLC. Oligocytidylic acids, ranging from dinucleotides to heptanucleotides, were obtained by RNase A digestion of poly(C). They were identified by MALDI-TOF mass spectrometry; it was confirmed that all of them corresponded to the general structure (Cp)(n)C>p, in which C>p indicates a 2',3'-cyclic phosphate. This is a confirmation of the proposed mechanism for RNase A, wherein the so-called hydrolytic (or second) step is in fact a special case of the reverse of transphosphorylation (first step). The patterns of cleavage for the oligonucleotide substrates show that the native enzyme has no special preference for endonucleolytic or exonucleolytic cleavage, whereas a mutant of the enzyme (K7Q/R10Q-RNase A) lacking p(2) (a phosphate binding subsite adjacent, on the 3' side, to the main phosphate binding site p(1)) shows a clear exonucleolytic pattern; a mutant (K66Q-RNase A) lacking p(0) (a phosphate binding subsite adjacent, on the 5' side, to the main phosphate binding site p(1)) shows a more endonucleolytic pattern. This indicates the important role played by the subsites on the preference for the bond cleaved. Molecular modeling shows that, in the case of the p(2) mutant, the amide group of glutamine can form a hydrogen bond with the 2',3'-cyclic terminal phosphate, whereas the distance to a 3',5'-phosphodiester bond is too long to form such a hydrogen bond. This could explain the preference for exonucleolytic cleavage shown by the p(2) mutant.