Design and development of novel spiro-oxindoles as potent antiproliferative agents using quantitative structure activity based Monte Carlo method, docking molecular, molecular dynamics, free energy calculations, and pharmacokinetics/toxicity studies

In this study, the Monte Carlo method was applied for quantitative structure-activity relationship of novel steroidal spiro-oxindoles as potent antiproliferative inhibitors against human breast cancer. The informa-tions derived from these models assist in the identification of the molecular fragments responsible for the increase and decrease in activity. The absorption, distribution, metabolism, excretion, and toxicity were predicted to help in drug development. Doxorubicin as a control, the best newly designed ligand P1, and compound 25 most active were docked in the binding site at three target receptor tyrosine kinases for behavior final assessment of the inhibitors studied, and also to determine the most selective receptor for our ligands. The results showed the good positioning of the designed ligands in the binding site of three target of crystal structure of epidermal growth factor receptors kinase (2J5F, 5GTY and 3IKA). Molecular dynamic simulations and free binding energy calculation were performed on two best target proteins. The results showed the good stability of the compounds and especially the P1 ligand and the role of van der waals interaction and electrostatics in the stability of the studied ligands. These results open several possibilities to develop new and more potent inhibitors against breast cancer. (c) 2023 Elsevier B.V. All rights reserved.