A 3D-QSAR model based screen for dihydropyridine-like compound library to identify inhibitors of amyloid beta (Aβ) production.

Abnormal accumulation of amyloid beta peptide (Aβ) is one of the hallmarks of Alzheimer's disease progression. Practical limitations such as cost , poor hit rates and a lack of well characterized targets are a major bottle neck in the in vitro screening of a large number of chemical libraries and profiling them to identify Aβ inhibitors. We used a limited set of 1,4 dihydropyridine (DHP)-like compounds from our model set (MS) of 24 compounds which inhibit Aβ as a training set and built 3D-QSAR (Three-dimensional Quantitative Structure-Activity Relationship) models using the Phase program (SchrÖdinger, USA). We developed a 3D-QSAR model that showed the best prediction for Aβ inhibition in the test set of compounds and used this model to screen a 1,043 DHP-like small library set of (LS) compounds. We found that our model can effectively predict potent hits at a very high rate and result in significant cost savings when screening larger libraries. We describe here our in silico model building strategy, model selection parameters and the chemical features that are useful for successful screening of DHP and DHP-like chemical libraries for Aβ inhibitors.