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The N-terminal sequence of the Smac (second-mitochondria derived activator) protein is known to be involved in binding to the BIR3 (Baculovirus IAP repeat) domain of the IAPs (inhibitors of apoptosis proteins), and antagonized their function. Short peptides derived from N-terminal residues of Smac have shown to sensitize cancer cells to chemotherapeutic agents. In this regard, small library including 6-mer peptides were designed using docking to the BIR3 domain of cIAP1  in silico . Molecular dynamics simulation studies were also done on top-scored hits (SmacAQ, SmacIQ) using Desmond 2017-2 for 150 ns simulation time. These two peptides were conveniently synthesized using solid phase peptide synthesis on Fmoc-Gln (Trt)-Wang resin. Furthermore, we encapsulated DOX (doxorubicin) and synthesized peptides in PLGA: PLGA-PEG (9:1) NPs (nanoparticles) followed by MD (molecular dynamic) studies to understand the NP structure and the interactions between either DOX or peptide with polymeric nanoparticles during 100 ns simulation. Finally, the cytotoxic activity of these peptides in combination with DOX against two cancer cell lines including MCF7 and C26 were investigated. As a result, we found that DOX or peptide-loaded NPs had stable structure during the simulation. MD simulation also showed that alanine at N-terminal of Smac could be replaced with isoleucine without alternation of biological activity which was in agreement with  in vitro  experiments. Moreover, NPs-SmacIQ and NPs-SmacAQ significantly enhanced the cytotoxicity effect of NPs-DOX  in vitro  ( p  &lt; 0.001). Communicated by Ramaswamy H. Sarma

Smac peptide and doxorubicin-encapsulated nanoparticles: design, preparation, computational molecular approach and in vitro studies on cancer cells