Computational modeling of drugs for Alzheimer’s disease: Design of serotonin 5-HT6 antagonists

Abstract

The 5-hydroxytryptamine receptor 6 (5-HT6R) represents one of the most avowed targets for alleviating cognitive, learning, and memory deficits related to Alzheimer’s disease (AD). Ligand- and structure-based computational modeling methods serve as main tools at the initial stages of drug discovery projects to underlie and to understand small molecule targeting of the receptor. Here, we describe the currently known 5-HT6R antagonists in clinical trials and at discovery stages. We analyze existing ligand-based information and disposable pharmacophore models, quantitative structure-activity relationship methods, usable crystal structure templates, homology models, and molecular docking approaches. Our goal is to provide the reader with guidelines on how to utilize the existing knowledge and ligand- and structure-based methods for the design of new 5-HT6R antagonists and to highlight advantages and limitations of corresponding approaches and computational modeling tools in the field of 5-HT6R drug design.