QSAR based docking studies of marine algal anticancer compounds as inhibitors of protein kinase B (PKBβ)

Marine algae are prolific source of bioactive secondary metabolites and are found to be active against different cancer cell lines. QSAR studies will explicate the significance of a particular class of descriptor in eliciting anticancer activity against a cancer type. Marine algal compounds showing anticancer activity against six different cancer cell lines namely MCF-7, A431, HeLa, HT-29, P388 and A549 taken from Seaweed metabolite database were subjected to comprehensive QSAR modeling studies. A hybrid-GA (genetic algorithm) optimization technique for descriptor space reduction and multiple linear regression analysis (MLR) approach was used as fitness functions. Cell lines HeLa and MCF-7 showed good statistical quality (R-2 similar to 0.75, Q(2) similar to 0.65) followed by A431, HT29 and P388 cell lines with reasonable statistical values (R-2 similar to 0.70, Q(2) similar to 0.60). The models developed were interpretable, with good statistical and predictive significance. Molecular descriptor analyses revealed that Baumann's alignment-independent topological descriptors had a major role in variation of activity along with other descriptors. Incidentally, earlier QSAR analysis on a variety of chemically diverse PKB alpha inhibitors revealed Baumann's alignment-independent topological descriptors that differentiated the molecules binding to Protein kinase B (PKB alpha) kinase or PH domain, hence a docking study of two crystal structures of PKB beta was performed for identification of novel ATP-competitive inhibitors of PKB beta. Five compounds had a good docking score and Callophycin A showed better ligand efficiency than other PKB beta inhibitors. Furthermore in silico pharmacokinetic and toxicity studies also showed that Callophycin A had a high drug score (0.85) compared to the other inhibitors. These results encourages discovering novel inhibitors for cancer therapeutic targets by screening metabolites from marine algae. (C) 2015 Elsevier B.V. All rights reserved.