Background: Inhibition of cancer cell migration is an appropriate strategy for the prevention of metastasis. The purpose of this study was to identify new carbonyl thioureas as inhibitors of gastric cancer cell migration. Methods: N1-(morpholin-4-yl ethyl)/phenyl/aralkyl-N3-(thiophene-2-carbonyl)/benzoyl thioureas (1-12) were synthesized by one-pot two step reaction and assessed for their effect on growth and migration of human adeno gastric stomach (AGS) cell lines through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and wound-healing assays. Ras homolog family member A (RhoA) is a guanosine tri-phosphatase (GTPase) oncogenic target with crucial role in gastric cell migration and accordingly molecular docking and molecular dynamics (MD) simulations were performed on RhoA by AutoDock4 and GROningen MAchine for chemical simulations (GROMACS5) software. Drug-likeness scores and pharmacokinetics properties were calculated by MolSoft tool through SwissADME (ADME: absorption, Distribution, Metabolism and Excretion) online server. Results: All of the compounds relatively inhibited wound-healing process after 24 h, whereas compound 4 exhibited comparable anti-migratory activity to cis-platin. Compound 4 might exhibit true migrastatic effect (6.25 μg/mL) without significant cytotoxicity. SwissADME data were indicative of high gastrointestinal (GI) absorption and with the exception of compounds 7 and 9, all the compounds had lower risk of producing efflux-based resistance. Docking and MD simulations provided stable binding model for top-scored derivative (compound 4) inside RhoA binding site near to the GTP-binding pocket. All the structural indices were converged in the MD simulations and free energy calculations showed appropriate accommodation inside the RhoA binding site. Bind trajectory analysis revealed no stable intermolecular H-bonds within simulation time and the complex was majorly stabilized through hydrophobic contacts. Conclusion: The results of the current study suggested that compound 4 may be an appropriate candidate for further development into selective small molecule GTPase inhibitors against gastric cancer metastasis.
Sagha et al. (Mon,) studied this question.