Rationalizing lead optimization by consensus 2D- CoMFA CoMSIA GRIND (3D) QSAR guided fragment hopping in search of γ-secretase inhibitors.
γ-Secretase (Gamma Secretase) is a potential drug target in Alzheimer's disease therapeutics. A sequel lead design study was undertaken on a series of bicyclononanes with an aim of identifying potent isofunctional chemotypes. Fragment-based bioisosteric replacement, which considers shape, chemistry, and electrostatics was carried out to mine over four million medicinally relevant fragments of Brood database. The resulting subset, thus, obtained was further mined using consensus QSAR developed from 2D and CoMFA, CoMSIA, GRIND (3D) QSAR predicted endpoints with superior statistical results. The employed consensus prediction and the predicted endpoint values were found to be in good agreement with the experimental values. The predictive ability of the generated model was validated using different statistical metrics, and similarity-based coverage estimation was carried out to define applicability boundaries. Few analogs designed, using the concept of bioisosterism, were found to be promising and could be considered for synthesis and subsequent screening.
Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata 700032, India.
Prabu
P
Manoharan
Nanda
N
Ghoshal
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results
D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases