Generating a homology model of the human M1 muscarinic receptor and the design of cognate modulators at this locus for the management of Alzheimer’s disease

Abstract

The link between Alzheimer’s disease and the M1 muscarinic receptor subtypes makes the latter a viable target for modulating the pathogenesis involved in the development of the disease. The aim of this project was to create a novel drug to modulate an in silico-created homology model of the M1 receptor to manage Alzheimer’s disease. The preliminary part of this study involved creation of a homology model of the M1 receptor. This was followed by analysis of the ligandbinding pocket and in silico design of novel molecules capable of modulating this proposed structure. SYBYL-X®, X-SCORE®, LigBuilder®, Visual Molecular Dynamics (VMD), Accelrys® Draw, Accelrys® Discovery Studio 3.5 and the Protein Data Bank were used to generate the results. A homology model for the M1 receptor was created. Analysis of the ligand binding pocket resulted in 12 varying conformers; that with optimal binding affinity was chosen to create a seed. This generated 200 molecules, classified into 12 chemical families, 124 of which were retained due to conformity to Lipinski’s Rules. Highest & lowest-ranked molecules in each chemical family were structurally-analysed, which yielded chemical moieties responsible for optimal chemical binding to the proposed ligand binding pocket. The de novo molecules created and optimized present viable leads for high-throughput screening in subsequent drug-design studies, potentially leading to identification of novel M1 muscarinic receptor subtype modulators for the use in managing Alzheimer’s disease.