Virtual screening approach for the discovery of selective 5α-reductase type II inhibitors for benign prostatic hyperplasia treatment.

Background: 5α-Reductase type II (5αR2) inhibition is a promising strategy for benign prostatic hyperplasia treatment. A computational approach including virtual screening, ligand-based 3D pharmacophore modeling, 2D quantitative structure-activity relationship and molecular docking simulations were adopted to develop novel inhibitors. Results: Hits were first filtered via the validated pharmacophore and 2D quantitative structure-activity relationship models. Docking on the recently determined cocrystallized structure of 5αR2 showed three promising hits. Visual inspection results were compared with finasteride ligand and dihydrotestosterone as reference, to explain the role of binding to Glu57 and Tyr91 for 5αR2 selective inhibition. Conclusion: Alignment between Hit 2 and finasteride in the binding pocket showed similar binding modes. The biological activity prediction showed antitumor and androgen targeting activity of the new hits.

New indole derivatives as multitarget anti-Alzheimer's agents: synthesis, biological evaluation and molecular dynamics.

Background: Alzheimer's disease is a neurological disorder that causes brain cells to shrink and die. Aim: Thirteen novel 'oxathiolanyl', 'pyrazolyl' and 'pyrimidinyl' indole derivatives were designed and synthesized as anti-Alzheimer's disease treatment. Method: In vitro enzyme assay was performed against both AChE and BChE enzymes. In addition, antioxidant assay and cytotoxicity on a normal cell line were determined. Molecular docking and dynamic simulations were conducted to confirm the binding mode in both esterases' active sites. In silico absorption, distribution, metabolism, excretion and toxicity studies were also carried out. Results & conclusion: Compounds 5, 7 and 11 exhibited superior inhibitory activity against acetylcholinesterase and butyrylcholinesterase, with IC50 values of 0.042 and 3.003 µM, 2.54 and 0.207 µM and 0.052 and 2.529 µM, respectively, compared with donepezil.

Design, synthesis and 3D QSAR based pharmacophore study of novel imatinib analogs as antitumor-apoptotic agents.

AIM: Imatinib possesses various mechanisms for combating cancer, making the development of imatinib analogs an attractive target for cancer research. METHOD: Two series of analogs were designed and synthesized, maintaining the essential pharmacophoric features in imatinib structure. The synthesized compounds were subjected to cell-based antiproliferative assays against nonsmall lung (A549) and colon cancer cell lines. In addition, flow cytometry cell cycle and caspase-3 colorimetric assays were performed. RESULTS: Most compounds showed potent anticancer activity against both cell lines with IC50 = 0.14-5.07 µM. Three compounds demonstrated ability to reinforce cell cycle arrest at G1 stage in a manner similar to imatinib. In addition, they induced apoptosis via activation of caspase-3.