Molecular dynamics study of protein mortalin and its mutants with anti-cancer agents flex hets

Mortalin is a protein that belongs to a family of heat shock proteins (Hsp70) and has been found to be overexpressed in cancer cell lines. Mortalin has been found to interact with tumor suppressor protein p53, thus inhibiting the role of p53 in cell cycle control and apoptosis. Abrogation of mortalin-p53 interaction is one pathway to inhibit the growth of cancer cells. Flexible heteroarotinoids (Flex-hets) compounds compete with p53-mortalin interaction and release p53. Flexible heteroarotinoids (Flex-hets) compounds are well known for the inhibition of cancer cells with very less toxicity to the normal cells. SHetA2, a parent compound of flex-hets and its analogues are known to significantly inhibit the growth of ovarian cancer cells A2780. Using docking and molecular dynamics techniques, two series of SHetA2 analogues were studied- 1). oxygen/sulfur containing analogues in the chroman ring of SHetA2 and 2). tetrahydroquinoline (THQ) containing analogues of SHetA2. Docking study shows that SHetA2 and its analogues bind to the hydrophobic binding pocket of substrate binding domain (SBD) in mortalin. Increasing the hydrophobicity in the chroman ring unit of the SHetA2 analogues and introduction of urea linker instead of thio-urea linker showed the better binding affinity. Having electron-withdrawing groups like -NO2 and -CF3 in ring B showed a better performance (high efficacy and low IC50). For the analogues with THQ units in ring A, compounds of series 3a-e, containing oxygen in ring A showed smaller IC50 and greater efficacy values than the parent compound, SHetA2. Cancer cell growth inhibition data from biological experiments shows that compounds with better binding energy have higher efficacy (maximum cancer cell inhibition) smaller value of IC50 (half maximum inhibitory concentration) values. Further, molecular dynamics simulation on mortalin mutants (S473A and T449A) shows that SHetA2 binds much stronger to the mutant S473A than to the wild type protein, which shows that mortalin as acceptor of SHetA2, which is in accordance with the biological experiments