Design and optimisation of novel Huperzine A analogues capable of modulating the acetylcholinesterase receptor for the management of Alzheimers disease

This is a de novo drug design study that aimed to create novel structures based on the alkaloid Huperzine A, capable of inhibiting the acetylcholinesterase (AChE) enzyme ligand binding pocket (AChE_LBP) for the management of Alzheimer’s disease. The X-ray crystallographic model of the Torpedo Californica AChE complexed to Huperzine A was identified from the Protein Data Bank (PDB ID 1VOT). Molecular visualisation and modelling was carried out using SYBYL® 1.2, in silico predicted ligand binding affinity (LBA) was quantified using XSCORE_V1.3 and de novo drug design was carried out using LIGBUILDER®V1.2. Two seed structures were constructed in SYBYL® 1.2 according to a methodology that took into account the relationship between molecular structure and biological activity as described in the literature. Based on SAR data derived from Huperzine A, the points considered to be critical for binding were retained in each seed and planted into the AChE_LBP with growth being allowed according to defined parameters of LIGBUILDER®V1.2. The implication of this study consequently is that novel structures compliant to Lipinski’s Rule of 5 may be promoted to second level drug design which could lead to identification of novel AChE inhibitors with better potency and a low side effect profile.   Key words: de novo drug design, Huperzine A, acetylcholinesterase, Alzheimer’s disease, Lipinski’s Rule of 5.