In silico identification of potential γ-secretase inhibitor of marine-algal origin: an anticancer intervention

Abstract

ABSTRACT Gamma secretase (GS) activates notch signalling pathway (NSP) by liberating the truncated notch intracellular domain (NICD). The NSP is associated with the cancer development and progression, which makes GS a potential therapeutic target. Now day’s marine compounds emerged as a major source of bioactive entity. The NSP inhibition potential of marine-algal compounds has not yet been studied. Thus, in the present study, we have used molecular docking, molecular dynamics (MD) simulations, principal component analysis (PCA) and free energy and binding energy calculations to identify the potential GS inhibitors of marine-algal origin. Laminarin showed better docking score (−12.72) compared to the known GS inhibitor DAPT (−9.2). Laminarin formed H-Bond interaction with the Asp257 and Asp385 required for the catalytic cleavage activity of gamma-secretase. It potentially stabilised the structural parameters (RMSD, RMSF, Rg and SASA) of GS catalytic subunit compared to DAPT during the MD simulation. The PCA and free energy calculation revealed conformationally and energetically stable Laminarin–GS complex formation. Laminarin showed lower binding energy (−44.75 kcal/mol) with GS catalytic subunit than DAPT (−20.92 kcal/mol). In conclusion, the present study provides a marine-algal compound as a novel potential GS inhibitor, which requires further validation in experimental model.