E-Pharmacophore Based Virtual Screening to Identify Agonist for PKA-Cα

Abstract

Owing to PKA-Cα unique functions in regulating tau splicing alternatively in neurons results in aggregation of tau which contributes to neurofibrillary tangles and taupathies generation a hallmark of Alzheimer’s disease (AD). PKACα also inhibits GSK3β thus it has been a therapeutic target for AD intervention. In this study, e-pharmacophore and multiple docking strategies were followed to propose a novel PKA-Cα agonists. Nine e-pharmacophores were developed from nine co-crystal structures such that all the critical pharmacophoric features involved in their bioactivity of PKA-Cα were effectively mapped. Rigid receptor docking (RRD) was performed with the library of PKA-Cα activators having 3512 shape screened compounds towards PKA-Cα. To derive the best leads, dock complexes were further subjected to QPLD, IFD and MM-GBSA calculations. PKA-Cα-lead1 dock complex was subjected to 50 ns MD simulations run. Comparative analysis between obtained 25 leads and 9 co-crystal ligands revealed three the best leads. Among the three, lead1 has the least docking score with lowest binding free energy with better binding orientation towards PKA-Cα. The constancy of PKA-Cα-lead1 interactions was revealed by 50 ns MD simulations run. Thus ADME predictions and results from RRD, QPLD, IFD and MD simulations affirmed that the proposed three leads might be used as a potent agonists for PKA-Cα.