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.

Little is known about establishment success of the arbuscular mycorrhizal fungal (AMF) inocula and their effects on a soil-indigenous community of AMF. In this study, we assessed the effect of introducing Rhizophagus irregularis DAOM-197198 in soil under field condition on the community composition of indigenous AMF in the roots of corn (Zea mays), soybean (Glycine max), and wheat (Triticum aestivum). Three field trials were conducted with inoculated and non-inoculated plots. Four to ten roots and their rhizosphere soil samples of two growth stages for corn and wheat, and one growing stage of soybean, were collected, totalling 122 root and soil samples. Root colonization was measured microscopically, and the fungal communities were determined by paired-end Illumina MiSeq amplicon sequencing using 18S rDNA marker. After quality trimming and merging of paired ends, 6.7 million sequences could be assigned to 414 different operational taxonomic units. These could be assigned to 68 virtual taxa (VT) using the AMF reference sequence database MaarjAM. The most abundant VT corresponded to R. irregularis. The inoculation treatment did not influence the presence of R. irregularis, or AMF community diversity in roots. This seems to indicate that inoculation with R. irregularis DAOM-197198 does not change the indigenous AMF community composition, probably because it is already present in high abundance naturally.

The epidermal growth factor receptor (EGFR) is part of a protein family that controls cell growth and development. Due to its importance, EGFR has been identified as a suitable target for creating novel drugs. For this research, we conducted a 2D-QSAR analysis on a set of 31 molecules derived from quinazoline, which exhibited inhibitory activity against human lung cancer. This investigation incorporated principal component analysis (PCA) and multiple linear regression (MLR), leading to the development of QSAR models with strong predictive capabilities (R ² = 0.745, R ²_adj = 0.723, MSE = 0.061, R ²_test = 0.941, and Q ²_cv = 0.669). The reliability of these models was confirmed through internal, external, Y-randomization, and applicability domain validations. Leveraging the predictions from the QSAR model, we designed 18 new molecules based on the modifications at the N-3 and C-6 positions of the quinazoline ring, with electronegative substituents at these positions fostering optimal polar interactions and hydrophobic contacts within the ATP-binding site of EGFR, significantly enhancing the inhibitory activity against the lung cancer cell line. Subsequently, ADMET predictions were conducted for these 18 compounds, revealing outstanding ADMET profiles. Molecular docking analyses were performed to investigate the interactions between the newly designed molecules-Pred15, Pred17, Pred20, Pred21-and the EGFR protein, indicating high affinity of these proposed compounds to EGFR. Furthermore, molecular dynamics (MD) simulations were utilized to assess the stability and binding modes of compounds Pred17, Pred20, and Pred21, reinforcing their potential as novel inhibitors against human lung cancer. Overall, our findings suggest that these investigated compounds can serve as effective inhibitors, showcasing the utility of our analytical and design approach in the identification of promising therapeutic agents.

Pseudomonas stutzeri phosphite dehydrogenase (PTDH) catalyzes the oxidation of phosphite to phosphate in the presence of NAD, resulting in the formation of NADH. The regeneration of NADH by PTDH is greater than any other enzyme due to the substantial change in the free energy of reaction (G°′ = − 63.3 kJ/mol). Presently, improving the stability of PTDH is for a great importance to ensure an economically viable reaction process to produce phosphite as a byproduct for agronomic applications. The binding site of NAD⁺ with PTDH includes thirty-four residues; eight of which have been previously mutated and characterized for their roles in catalysis. In the present study, the unexplored twenty-six key residues involved in the binding of NAD⁺ were subjected to in silico mutagenesis based on the physicochemical properties of the amino acids. The effects of these mutations on the structure, stability, activity, and interaction of PTDH with NAD⁺ were investigated using molecular docking, molecular dynamics simulations, free energy calculations, and secondary structure analysis. We identified seven novel mutations, A155I, G157I, L217I, P235A, V262I, I293A, and I293L, that reduce the compactness of the protein while improving PTDH stability and binding to NAD⁺.

One of the characteristic features of cancer is angiogenesis, the process by which new, aberrant blood vessels are formed from pre-existing blood vessels. The process of angiogenesis begins when VEGF binds to its receptor, the VEGF receptor (VEGFR). The formation of new blood vessels provides nutrients that can promote the growth of cancer cells. When it comes to new blood vessel formation, VEGFR2 is a critical player. Therefore, inhibiting VEGFR2 is an effective way to target angiogenesis in cancer treatment. The aim of our research was to find new VEGFR-2 inhibitors by performing a virtual screening of 13313 from African natural compounds using different in silico techniques. Using molecular docking calculations and ADMET properties, we identified four compounds that exhibited a binding affinity ranging from −11.0 kcal/mol to −11.5 Kcal/mol when bound to VEGFR-2. These four compounds were further analyzed with 100 ns simulations to determine their stability and binding energy using the MM-PBSA method. After comparing the compounds with Regorafenib, a drug approved for anti-angiogenesis treatment, it was found that all the candidates (EANPDB 252, NANPDB 4577, and NANPDB 4580), with the exception of EANPDB 76, could target VEGFR-2 similarly effectively to Regorafenib. Therefore, we recommend three of these agents for anti-angiogenesis treatment because they are likely to deactivate VEGFR-2 and thus inhibit angiogenesis. However, it should be noted that the safety and suitability of these agents for clinical use needs further investigation, as the computer-assisted study did not include in vitro or in vivo experiments.

More people are being diagnosed with resistant breast cancer, increasing the urgency of developing new effective treatments. Several lines of evidence suggest that blocking the kinase activity of VEGFR-2 reduces angiogenesis and slows tumor growth. In this study, we developed novel VEGFR-2 inhibitors based on the triazolopyrazine template by using comparative molecular field analysis (CoMFA) and molecular similarity indices (CoMSIA) models for 3D-QSAR analysis of 23 triazolopyrazine-based compounds against breast cancer cell lines (MCF -7). Both CoMFA (Q² = 0.575; R² = 0.936, R_pred² = 0.956) and CoMSIA/SE (Q² = 0.575; R² = 0.936, R_pred² = 0.847) results demonstrate the robustness and stability of the constructed model. Six novel compounds with potent inhibitory activity were carefully designed, and screening of ADMET properties revealed their good oral bioavailability and ability to diffuse through various biological barriers. When compared with the most active molecule in the data set and with Foretinib (breast cancer drug), molecular docking revealed that the six designed compounds had strengthened affinity (−8.9 to −10 kcal/mol) to VEGFR-2. Molecular Dynamics Simulations and MMPBSA calculations were applied to the selected compound T01 with the highest predicted inhibitory activity, confirming its stability in the active pocket of VEGFR-2 over 100 ns. The present results provided the basis for the chemical synthesis of new compounds with improved inhibitory properties against the breast cancer cell line (MCF -7).