Target specific proteochemometric model development for BACE1 - protein flexibility and structural water are critical in virtual screening.
BACE1 is an attractive target in Alzheimer's disease (AD) treatment. A rational drug design effort for the inhibition of BACE1 is actively pursued by researchers in both academic and pharmaceutical industries. This continued effort led to the steady accumulation of BACE1 crystal structures, co-complexed with different classes of inhibitors. This wealth of information is used in this study to develop target specific proteochemometric models and these models are exploited for predicting the prospective BACE1 inhibitors. The models developed in this study have performed excellently in predicting the computationally generated poses, separately obtained from single and ensemble docking approaches. The simple protein-ligand contact (SPLC) model outperforms other sophisticated high end models, in virtual screening performance, developed during this study. In an attempt to account for BACE1 protein active site flexibility information in predictive models, we included the change in the area of solvent accessible surface and the change in the volume of solvent accessible surface in our models. The ensemble and single receptor docking results obtained from this study indicate that the structural water mediated interactions improve the virtual screening results. Also, these waters are essential for recapitulating bioactive conformation during docking study. The proteochemometric models developed in this study can be used for the prediction of BACE1 inhibitors, during the early stage of AD drug discovery.
Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata 700032, India. nghoshal@iicb.res.in.
Prabu
P
Manoharan
Kiranmai
K
Chennoju
Nanda
N
Ghoshal
D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry*; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry*; D020134:Catalytic Domain; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy; D011480:Protease Inhibitors / Q000737:chemistry; D011485:Protein Binding; D012372:ROC Curve; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
D008024:Ligands; D011480:Protease Inhibitors; D014867:Water; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human