In silico ligand-based modeling of hBACE-1 inhibitors

Abstract

Alzheimer's disease (AD) is a chronic neurodegenerative disease affecting more than 30 million people worldwide. Development of small molecule inhibitors of human β-secretase 1 (hBACE-1) is being the focus of pharmaceutical industry for the past 15-20 years. Here, we successfully applied multiple ligand-based in silico modeling techniques to understand the inhibitory activities of a diverse set of small molecule hBACE-1 inhibitors reported in the scientific literature. Strikingly, the use of only a small subset of 230 (13%) molecules allowed us to develop quality models that performed reasonably well on the validation set of 1476 (87%) inhibitors. Varying the descriptor sets and the complexity of the modeling techniques resulted in only minor improvements to the model's performance. The current results demonstrate that predictive models can be built by choosing appropriate modeling techniques in spite of using small datasets consisting of diverse chemical classes, a scenario typical in triaging of high-throughput screening (HTS) results to identify false negatives. We hope that these encouraging results will help the community to develop more predictive models that would support research efforts for the debilitating Alzheimer's disease. Additonally, the integrated diversity of the techniques employed will stimulate scientists in the field to use in silico statistical modeling techniques like these to derive better models to help advance the drug discovery projects faster.

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Multiple ligand based QSAR approaches with increasing modeling sophistication and descriptor information content were used to develop qualitative classification and quantitative regression models using experimental IC₅₀′s reported for hBACE-1 small molecule inhibitors. The statistical modeling outcome and analysis provides a framework for extending this workflow for other therapeutic targets as well as avenues to further the lead identification and lead optimization of small molecule hBACE-1 inhibitors

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