Molecular Dynamics simulations of Inhibitor of Apoptosis Proteins and identification of potential small molecule inhibitors.
Chemotherapeutic resistance due to over expression of Inhibitor of Apoptosis Proteins (IAPs) XIAP, survivin and livin has been observed in various cancers. In the current study, Molecular Dynamics (MD) simulations were carried out for all three IAPs and a common ligand binding scaffold was identified. Further, a novel sequence based motif specific to these IAPs was designed. SMAC is an endogenous inhibitor of IAPs. Screening of ChemBank for compounds similar to lead SMAC-non-peptidomimetics yielded a cemadotin related compound NCIMech_000654. Cemadotin is a derivative of natural anti-tumor peptide dolastatin-15; hence these compounds were docked against all three IAPs. Based on our analysis, we propose that NCIMech_000654/dolastatin-15/cemadotin derivatives may be investigated for their potential in inhibiting XIAP, survivin and livin.
Centre for Biotechnology, Anna University, Chennai 600 025, India.
Jayanthi
J
Jayakumar
Centre for Biotechnology, Anna University, Chennai 600 025, India. Electronic address: s_anishetty@yahoo.co.uk.
Sharmila
S
Anishetty
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C107489:BIRC5 protein, human; C419866:BIRC7 protein, human; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D009842:Oligopeptides; D054852:Small Molecule Libraries; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein; C094621:cemadotin
Cancer; Inhibitor of Apoptosis Proteins (IAPs); MD simulations; SMAC; Small molecule inhibitors