Virtual screening for potential inhibitors of Mcl-1 conformations sampled by normal modes, molecular dynamics, and nuclear magnetic resonance

Glantz-Gashai, Yitav; Meirson, Tomer; Reuveni, Eli; Samson, Abraham O

Interestingly, two of these, exemestane and lenvatinib, are clinically used and approved for the treatment of cancer. Exemestane is a third-generation aromatase inhibitor administered in breast cancer, 41 and lenvatinib is a vascular endothelial growth factor receptor 1 (VEGFR1), VEGFR2, and VEGFR3 kinase inhibitor administered in thyroid cancer. 42 As such, exemestane and lenvatinib are favorable candidates for Mcl-1-targeted cancer therapies. Other drugs among the top 10 ligands include levorphanol, dextromethorphan, and sibutramine, which are morphine-like opioids with some noradrenergic and serotonergic activity. Notably, dextromethorphan is sometimes used to dull pain in cancer, and several clinical trials are currently evaluating its effect in peripheral neuropathy management (ie, ClinicalTrials.gov ID NCT02271893). Dextromethorphan could have an unexpected effect on the outcome of the chemotherapy treatment. Mirtazapine, cyproheptadine, oxcarbazepine, and epinastine are tricyclic compounds with histaminergic and serotonergic activity used to control pain and depression and as antiemetics in cancer. Notably, several clinical trials are currently evaluating them in palliative cancer management (ie, ClinicalTrials.gov IDs NCT01725048 and NCT02336750). If indeed Mcl-1 activity is experimentally shown, then these drugs could serve as adjuvants for cancer therapies. Finally, darifenacin is a muscarinic agonist used for urinary incontinence with little or no known relationship to cancer. Zinc69705019 (-6.65) Zinc78946317 (-8.11) Zinc48345734 (-6.73) 7