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Objectives: By 2030, prostate cancer is estimated to account for 1.7 million new cases and 499,000 deaths. The objectives of this research were to create a model revealing the activity of thiosemicarbazone-indole compounds as anticancer agents against the PC3 cell line; perform docking analysis between the compounds and the target enzyme; and predict the pharmacokinetics and drug-likeness of the compounds under investigation., Methods: The quantitative structureactivity relationship (QSAR) method was used to build the model; molecular docking between the compounds and the target enzyme was performed; and the drug-likeness and pharmacokinetics of the inhibiting compounds was examined., Results: The genetic function algorithm-multilinear regression approach was used for building the QSAR model. Build model 1 had the best performance, with R 2 (coefficient of determination) = 0.972517, R adj (adjusted R-squared) = 0.964665, (CRp 2 ) = 0.780922, and LOF (leave-one-out cross-validation) = 0.076524, demonstrated strongly indicated by the molecular descriptors. SHBd, SsCH3, JGI2, and RDF60P were highly dependent on proliferative activity. Compounds ID 7 and 22 had the potential to act as androgen receptor inhibitors, as suggested by molecular docking studies between the drugs and their target enzymes. Compounds ID 7 and 22 exhibited binding scores of -8.5 kcal/mol and -8.8 kcal/mol, respectively. The approved maximum medication molecules for oral bioavailability included the molecules with IDs 7 and 22., Conclusion: This research provides valuable insights into the relationships among molecular descriptors, potential inhibitors, and pharmacokinetic properties in the treatment of PC3. These findings may contribute to the understanding and potential development of new therapeutic options for prostate cancer patients., (© 2024 The Authors.)

Objectives: Diabetes places a substantial economic burden on countries worldwide. The costs associated with diabetes management, including healthcare services, medications, monitoring equipment, and productivity losses, are substantial. The International Diabetes Federation has estimated that global healthcare expenditures associated with diabetes and its complications exceed hundreds of billions of dollars annually. Therefore, a critical need exists to develop drugs that are highly effective, affordable, and easily accessible to society., Methods: This study explored the structural modification of 1,4-DHP derivatives to identify specific α-amylase inhibitors, with the aim of developing more effective and accessible drugs for diabetes. We evaluated the activity and binding ability of the designed compounds. In addition, we performed drug-likeness and pharmacokinetic studies on the modified compounds., Results: Equation (1) had the highest accuracy, on the basis of internal and external assessment parameters, including R 2 int  = 0.852, R 2 adj  = 0.803, Q 2 cv  = 0.731, and R 2 ext  = 0.884. Moreover, the five potent analogs identified through structure-based drug design demonstrated a more favorable interaction than observed for the template or acarbose. Additionally, comprehensive studies on the drug-like properties and pharmacokinetics of the designed compounds supported their oral safety and favorable pharmacokinetic profiles., Conclusions: The designed analogs show promise for developing new hypoglycemic agents. Their positive attributes and performance suggest that they may potentially serve as candidates for further research in improving treatments for high blood sugar-associated conditions., (© 2023 The Authors.)

Objectives: Breast tumor is ranked as the most common tumor type identified among women globally with over 1.7 million cases annually, representing 11.9% of the total number of cancer cases. Approved anti-breast tumor drugs exhibit several side effects and some patients develop resistance during the early treatment stage. This study aimed to use an in-silico approach to identify and design potential therapeutic agents., Methods: Robust 3D-QSAR models were developed using quinazoline-4(3H)-one analogs as EGFR inhibitors. The best model was then selected based on statistical parameters and was subsequently used to design more potent therapeutic agents. Molecular docking simulation was executed using the data set and the designed compounds to identify lead compounds which were further screened by pharmacokinetic profiling by applying SwissADME and pkCSM software., Results: Internal validations of the best CoMFA and CoMSIA models (R 2  = 0.855 and 0.895; Q 2  = 0.570 and 0.599) passed the threshold values for the establishment of a consistent QSAR model. The constructed models were further validated externally using six compounds as a test set, thus revealing a satisfactory predicted correlation coefficient (R 2 pred  = 0.657 and 0.681). The CoMSIA_SHE models with the best statistical parameters were further subjected to applicability domain checks and only three influentials were detected. These were then utilized to design five novel compounds with activities ranging from 5.62 to 6.03. Molecular docking studies confirmed that compounds 20 to 26, with docking scores ranging from -163.729 to -169.796, represented lead compounds with higher docking scores compared to Gefitinib (-127.495). Furthermore, the designed compounds exhibited better docking scores ranging from -171.379 to -179.138., Conclusions: Pharmacological studies identified compounds 20, 24 26 and the designed compounds 2, 3, 5 as feasible drug candidates. However, these theoretical findings should now be validated experimentally., (© 2023 [The Author/The Authors].)

Objectives: The V600E-BRAF protein kinase is an attractive and essential therapeutic target in melanoma and other tumors. However, because of its resistance to the known inhibitors and side effects of some identified inhibitors, new potent inhibitors need to be identified., Methods: In the present work, in silico strategies such as the molecular docking simulation, DFT (Density-Functional-Theory) computations, and pharmacokinetic evaluation were used to determine potential V600E-BRAF inhibitors from a set of 31 synthesized novel flavone-based arylamides., Results: The docking result demonstrated that four compounds (10, 11, 28, and 31) had acceptable docking scores (MolDock score of -167.523 kcal mol -1 , -158.168 kcal mol -1 , -160.581 kcal mol -1 ,-162.302 kcal mol -1 , and a Rerank score of -124.365, -129.365, -135.878 and -117.081, respectively) appeared as most active and potent V600E-BRAF inhibitors that topped vemurafenib (-158.139 and -118.607 kcal mol -1 ). The appearance of H-bonds and hydrophobic interactions with essential residues for V600E-BRAF proved the high stability of these complexes. The energy for the frontier molecular orbitals such as HOMO, LUMO, energy gap, and other reactivity parameters was computed using DFT. The frontier molecular-orbital surfaces and electrostatic potentials (EPs) were investigated to demonstrate the charge-density distributions that might be linked to anticancer activity. Similarly, the chosen compounds revealed superior pharmacological properties according to the drug-likeness rules (bioavailability) and pharmacokinetic properties., Conclusion: The chosen compounds were recognized as potent V600E-BRAF inhibitors with superior pharmacokinetic properties and could be promising cancer drug candidates., (© 2023 [The Author/The Authors].)

Objectives: V600E-BRAF kinase is an essential therapeutic target in melanoma and other types of tumors. Because of its resistance to known inhibitors and the adverse effects of some identified inhibitors, investigation of new potent inhibitors is necessary., Methods: In the present work, in silico strategies such as molecular docking simulation, pharmacokinetic evaluation, and density functional theory (DFT) computations were used to identify potential V600E-BRAF inhibitors from a set of 72 anticancer compounds in the PubChem database., Results: Five top-ranked molecules (12, 15, 30, 31, and 35) with excellent docking scores (MolDock score ≥90 kcal mol -1 , Rerank score ≥60 kcal mol -1 ) were selected. Several potential binding interactions were discovered between the molecules and V600E-BRAF . The formation of H-bonds and hydrophobic interactions with essential residues of V600E-BRAF suggested the high stability of these complexes. The selected compounds had excellent pharmacological properties according to the drug likeness rules (bioavailability) and pharmacokinetic properties. Similarly, the energy for the frontier molecular orbitals, such as the HOMO, LUMO, energy gap, and other reactivity parameters, was computed with DFT. The frontier molecular orbital surfaces and electrostatic potentials were investigated to demonstrate the charge-density distributions potentially associated with anticancer activity., Conclusion: The identified compounds were found to be potent hit compounds for V600E-BRAF inhibition with superior pharmacokinetic properties; therefore, they may be promising cancer drug candidates., (© 2023 [The Author/The Authors].)

Objective: This research aims to develop a mathematical model that relates the structural features of noscapine with anti-tumor activity, to explains the mode of binding between noscapine compounds and the target receptor tubulin by docking analysis. By considering the results of docking analysis and predictions of pharmacokinetic properties/drug likeness, we designed novel noscapine compounds as anti-tumor agents against pancreatic cancer., Methods: We used an in silico quantitative structure-activity relationship (QSAR) approach, molecular docking analysis and online tools for pharmacokinetics and drug likeness prediction to develop novel compounds., Results: A QSAR model with good validations parameters and quality of fit (R 2  = 0.9731, Q 2 CV  = 0.9434, R 2 adj  = 0.9647 and R 2 test set  = 0.8343) was built utilizing 70% of the dataset as a training set and the remaining 30% as an external validation to ascertain its predictive capability. Three novel compounds were designed: D3, D4 and D6 with binding scores of -11.2, -10.2 and 10.6 kcal/mol, respectively, exhibiting high affinity towards the tubulin receptor than the template (parent compound) and the co-crystallized ligand (E∗) with a binding score of 9.2 kcal/mol., Conclusion: The QSAR approach and molecular docking analysis is an important approach for modern drug discovery. Pharmacokinetics studies of the selected novel compounds revealed good drug properties and can be used as candidate compounds for the development of anti-tumor agents for pancreatic cancer., (© 2022 [The Author/The Authors].)