Abstract
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•Sorcin is a calcium binding protein that has a key role in MDR in human cancers.•Binding basis of the interactions of reported Sorcin inhibitors were elucidated.•Docking and MD simulation approaches identified potential Sorcin inhibitors.•Screened information can enable the establishment of therapeutic solution.
Sorcin (SOluble Resistance-related Calcium bInding proteiN) is a calcium binding protein that plays a key role in multidrug resistance (MDR) in human cancers. This study aimed at understanding the binding mechanism and structural basis for the interaction of structurally and functionally unrelated chemotherapeutic agent, namely doxorubicin, etoposide, omacetaxine mepesuccinate and paclitaxel with Sorcin by utilizing docking and molecular dynamic simulation approaches. The docking evaluation of etoposide, omacetaxine mepesuccinate and paclitaxel have shown a high affinity binding with Sorcin at the Ca2+-binding C-terminal domain (SCBD) in a comparable mode and affinity of binding to doxorubicin. Moreover, all of the docked compounds were shown to interact both hydrophilically and hydrophobically with the same residues within the active pocket which is located at interface of the Sorcin and collectively formed by EF5 loop, G helix and EF4 loop. However, the MD simulations revealed that the dynamics of Sorcin structure is different in the presence of the compounds when compared and contrasted to the Apo Sorcin, particularly in the first 25 ns, after which each system gained considerable structure stability. The difference in dynamics might be the outcome of high N and C-terminal flexibility that seem not to disturb compounds binding conformation but more likely is affecting chemical interaction network by breaking and establishing old and new hydrogen bonds, respectively. This detailed mechanistic understanding of different chemotherapeutic agents binding to Sorcin might be useful to open windows for designing and developing new inhibitors that are potentially capable of reversing the MDR in human cancers.