BACKGROUND - OBJECTIVES: Akt, a serin/threonin protein kinase, is a critical key in cell survival and proliferation. Allosteric inhibitors regulate aberrant kinase activity by stabilizing the protein in the inactive conformation. The aim of study was to discover novel scaffolds from optimal source for Akt1 inhibitors.
METHOD: Modeling approaches namely 3D-pharmacophore, QSAR, docking were performed by LeadIT 2.18, SybylX 2.0, MOE 2008.10 software.
RESULTS: A set of 135 structures from 5 key scaffolds was collected to generate and select the best 3Dpharmacophore model. 3D-database screening and 2D-QSAR were carried out. The result was a 5-feature pharmacophore model including 3 points of aromatic, 1 point of H-bond acceptor and metal ligation, 1 point of hydrophobic feature. Docking modeling results indicated that Trp80, a crucial amino acid related to mechanism keeps the inactive conformation of Akt1, often interacts π-π stacking with aromatic feature. The 2D QSAR model with 6 descriptors, R2 = 0,81 > 0,5 and RMSE = 0,39 < 0,5 was created. During the virtual screening and 2DQSAR, 44 novel compounds were selected with 2 novel scaffolds and 2 used drugs were showed as the hits of allosteric Akt1 inhibitors.
CONCLUSION: With these computational studies, the results suggested the 2 novel scaffolds and 2 approval drugs could be considered as hit/lead of allosteric Akt1 inhibitors and could perform the bioassay and next its further optimization.
