Computational analysis of bevacizumab binding with protein receptors for its potential anticancer activity.

Breast cancer poses a significant global challenge, prompting researchers to explore novel approaches for potential treatments. In this study, we investigated the binding free energy (ΔG) of bevacizumab, an anti-cancer therapy targeting angiogenesis through the inhibition of vascular endothelial growth factor (VEGF), with various proto-oncogenes including CDK4, EGFR, frizzled, IGFR, OmoMYC, and KIT. Our in-silico investigation revealed that hydrogen bonding is pivotal in inducing conformational changes within the DNA structure, impeding its replication and preventing cell death. Molecular docking results revealed the presence of crucial hydrogen bonds and supported the formation of stable bevacizumab complexes. The molecular docking scores for the tested complexes were CDK4 (Score = -7.2 kcal/mol), EGFR (Score = -8.5 kcal/mol), frizzled (Score = -6.9 kcal/mol), IGFR (Score = -7.8 kcal/mol), KIT (Score = -6.5 kcal/mol), and MYC (Score = -8.3 kcal/mol). The binding mode demonstrated vital hydrogen bonds correlated with the observed energy gap. Notably, the calculated binding free energies of the tested compounds are as follows: CDK4 (ΔG = 24275.195 ± 6411.293 kJ/mol), EGFR (ΔG = 363273.625 ± 8731.466 kJ/mol), frizzled (ΔG = 181751.990 ± 28438.515 kJ/mol), IGFR (ΔG = 162414.725 ± 10728.367 kJ/mol), KIT (ΔG = 40162.585 ± 4331.017 kJ/mol), and MYC (ΔG = 434783.463 ± 53989.676 kJ/mol). Furthermore, through extensive 100 ns MD simulations, we observed the formation of a stable bevacizumab complex structure. The simulations confirmed the stability of the bevacizumab complex with the proto-oncogenes. The results of this study highlight the potential of bevacizumab complex as a promising candidate for anticancer treatment. The identification of hydrogen bonding, along with the calculated binding free energies and molecular docking scores, provides valuable insights into the molecular interactions and stability of the bevacizumab complexes. These findings and the extensive MD simulations open new avenues for future research and development of bevacizumab as a targeted therapy for breast cancer and other related malignancies.Communicated by Ramaswamy H. Sarma.

QSAR-driven screening uncovers and designs novel pyrimidine-4,6-diamine derivatives as potent JAK3 inhibitors.

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.Communicated by Ramaswamy H. Sarma.

Discovery of 1-(5-bromopyrazin-2-yl)-1-[3-(trifluoromethyl)benzyl]urea as a promising anticancer drug via synthesis, characterization, biological screening, and computational studies.

Cancer and different types of tumors are still the most resistant diseases to available therapeutic agents. Finding a highly effective anticancer drug is the first target and concern of thousands of drug designers. In our attempts to address this concern, a new pyrazine derivative, 1-(5-bromopyrazin-2-yl)-1-[3-(trifluoromethyl)benzyl]urea (BPU), was designed via structural optimization and synthesized to investigate its anticancer/antitumor potential. The in-vitro anticancer properties of BPU were evaluated by MTT assay using selected cell lines, including the Jurkat, HeLa, and MCF-7 cells. The Jurkat cells were chosen to study the effect of BPU on cell cycle analysis using flow cytometry technique. BPU exhibited an effective cytotoxic ability in all the three cell lines assessed. It was found to be more prominent with the Jurkat cell line (IC50 = 4.64 ± 0.08 µM). When it was subjected to cell cycle analysis, this compound effectively arrested cell cycle progression in the sub-G1 phase. Upon evaluating the antiangiogenic potential of BPU via the in-vivo/ex-vivo shell-less chick chorioallantoic membrane (CAM) assays, the compound demonstrated very significant findings, revealing a complementary supportive action for the compound to act as a potent anticancer agent through inhibiting blood vessel formation in tumor tissues. Moreover, the docking energy of BPU computationally scored - 9.0 kcal/mol with the human matrix metalloproteinase 2 (MMP-2) and - 7.8 kcal/mol with the human matrix metalloproteinase 9 (MMP-9), denoting promising binding results as compared to the existing drugs for cancer therapy. The molecular dynamics (MD) simulation outcomes showed that BPU could effectively bind to the previously-proposed catalytic sites of both MMP-2 and MMP-9 enzymes with relatively stable statuses and good inhibitory binding abilities and parameters. Our findings suggest that the compound BPU could be a promising anticancer agent since it effectively inhibited cell proliferation and can be selected for further in-vitro and in-vivo investigations. In addition, the current results can be extensively validated by conducting wet-lab analysis so as to develop novel and better derivatives of BPU for cancer therapy with much less side effects and higher activities.

Isoform switching leads to downregulation of cytokine producing genes in estrogen receptor positive breast cancer.

Objective: Estrogen receptor breast cancer (BC) is characterized by the expression of estrogen receptors. It is the most common cancer among women, with an incidence rate of 2.26 million cases worldwide. The aim of this study was to identify differentially expressed genes and isoform switching between estrogen receptor positive and triple negative BC samples. Methods: The data were collected from ArrayExpress, followed by preprocessing and subsequent mapping from HISAT2. Read quantification was performed by StringTie, and then R package ballgown was used to perform differential expression analysis. Functional enrichment analysis was conducted using Enrichr, and then immune genes were shortlisted based on the ScType marker database. Isoform switch analysis was also performed using the IsoformSwitchAnalyzeR package. Results: A total of 9,771 differentially expressed genes were identified, of which 86 were upregulated and 117 were downregulated. Six genes were identified as mainly associated with estrogen receptor positive BC, while a novel set of ten genes were found which have not previously been reported in estrogen receptor positive BC. Furthermore, alternative splicing and subsequent isoform usage in the immune system related genes were determined. Conclusion: This study identified the differential usage of isoforms in the immune system related genes in cancer cells that suggest immunosuppression due to the dysregulation of CXCR chemokine receptor binding, iron ion binding, and cytokine activity.

In silico identification of 1,2,4-triazoles as potential Candida Albicans inhibitors using 3D-QSAR, molecular docking, molecular dynamics simulations, and ADMET profiling.

Fluconazole and Voriconazole are individual antifungal inhibitors broadly adopted for treating fungal infections, including Candida Albicans. Unfortunately, these medicines clinically used have significant side effects. Consequently, the improvement of safer and better therapy became more indispensable. In this study, a set of 27 1,2,4-triazole compounds have been tested as potential Candida Albicans inhibitors by using different theoretical methods. The created comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) contour maps significantly impacted the development of novel Candida Albicans inhibitors with valuable activities. The mode of interactions between the 1,2,4-triazole inhibitors and the targeted receptor was studied by molecular docking simulation. The proposed new molecule P1 showed satisfied stability in the active pocket of the targeted receptor compared to the more active molecule in the dataset compared to Fluconazole medication. Meanwhile, the binding energy obtained by molecular docking for molecule P1 is - 9.3 kcal/mol compared with - 6.7 kcal/mol for Fluconazole medication. Also, MM/GBSA value obtained by molecular dynamics simulations at 100 ns for molecule P1 is - 33.34 kcal/mol compared with - 15.85 kcal/mol for Fluconazole medication. In addition, molecule P1 showed good oral bioavailability and was non-toxic according to ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties. Therefore, the results indicated compound P1 might be a future inhibitor of Candida Albicans infection.

Computational approach investigation bioactive molecules from Saussurea Costus plant as SARS-CoV-2 main protease inhibitors using reverse docking, molecular dynamics simulation, and pharmacokinetic ADMET parameters.

SARS-COV-2 virus causes (COVID-19) disease; it has become a global pandemic since 2019 and has negatively affected all aspects of human life. Scientists have made great efforts to find a reliable cure, vaccine, or treatment for this emerging disease. Efforts have been directed towards using medicinal plants as alternative medicines, as the active chemical compounds in them have been discovered as potential antiviral or anti-inflammatory agents. In this research, the potential of Saussurea costus (S. Costus) or QUST Al Hindi chemical consistent as potential antiviral agents was investigated by using computational methods such as Reverse Docking, ADMET, and Molecular Dynamics with different proteases COVID-19 such as PDB: 2GZ9; 6LU7; 7AOL, 6Y2E, 6Y84. The results of Reverse Docking the complex between 6LU7 proteases and Cynaropicrin compound being the best complex, as the same result, is achieved by molecular dynamics. Also, the toxicity testing result from ADMET method proved that the complex is the least toxic and the safest possible drug. In addition, 6LU7-Cynaropicrin complex obeyed Lipinski rule; it formed ≤5 H-bond donors and ≤10 H bond acceptors, MW < 500 Daltons, and octanol/water partition coefficient <5.

In silico detection of potential inhibitors from vitamins and their derivatives compounds against SARS-CoV-2 main protease by using molecular docking, molecular dynamic simulation and ADMET profiling.

COVID-19 is a new infectious disease caused by SARS-COV-2 virus of the coronavirus Family. The identification of drugs against this serious infection is a significant requirement due to the rapid rise in the positive cases and deaths around the world. With this concept, a molecular docking analysis for vitamins and their derivatives (28 molecules) with the active site of SARS-CoV-2 main protease was carried out. The results of molecular docking indicate that the structures with best binding energy in the binding site of the studied enzyme (lowest energy level) are observed for the compounds; Folacin, Riboflavin, and Phylloquinone oxide (Vitamin K1 oxide). A Molecular Dynamic simulation was carried out to study the binding stability for the selected vitamins with the active site of SARS-CoV-2 main protease enzyme. Molecular Dynamic shows that Phylloquinone oxide and Folacin are quite unstable in binding to SARS-CoV-2 main protease, while the Riboflavin is comparatively rigid. The higher fluctuations in Phylloquinone oxide and Folacin indicate that they may not fit very well into the binding site. As expected, the Phylloquinone oxide exhibits small number of H-bonds with protein and Folacin does not form a good interaction with protein. Riboflavin exhibits the highest number of Hydrogen bonds and forms consistent interactions with protein. Additionally, this molecule respect the conditions mentioned in Lipinski's rule and have acceptable ADMET proprieties which indicates that Riboflavin (Vitamin B2) could be interesting for the antiviral treatment of COVID-19.

Camphor, Artemisinin and Sumac Phytochemicals as inhibitors against COVID-19: Computational approach.

Covid-19 is an emerging infectious disease caused by coronavirus SARS-CoV-2. Due to the rapid rise in deaths resulted from this infection all around the world, the identification of drugs against this new coronavirus is an important requirement. Among the drugs that can fight this type of infection; natural products are substances that serve as sources of beneficial chemical molecules for the development of effective therapies. In this study, Camphor, Artemisinin and 14 Sumac phytochemicals were docked in the active site of SARS-CoV-2 main protease (PDB code: 6LU7). We have also performed molecular dynamic simulation at 100 ns with MM-GBSA/PBSA analysis for the structures with the best affinity in the binding site of the studied enzyme (Hinokiflavone and Myricetin) after docking calculations to consider parameters like RMSD, covariance, PCA, radius of gyration, potential energy, temperature and pressure. The result indicates that Hinokiflavone and Myricetin are the structures with best affinity and stability in the binding site of the studied enzyme and they respect the conditions mentioned in Lipinski's rule and have acceptable ADMET proprieties; so, these compounds have important pharmacokinetic properties and bioavailability, and they could have more potent antiviral treatment of COVID-19 than the other studied compounds.