Abstract
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.
Highlights
Alzheimer's disease is the most common cause of dementia (Akhondzadeh and Abbasi, 2006) characterised by the build-up in the brain of protein rich plaques and leading to decreased cerebral nerve cell connectivity culminating in the death of nerve cells and loss of brain tissue (Wang et al, 2006a)
All 15 molecules chosen from Seed A and all 45 molecules chosen from Seed B were Lipinski rule compliant
The best molecule from the top 15 molecules chosen from Seed A is molecule number 6 having a pKd of 8.82 and a LBE of 126.999 kcal mol-1
Summary
Alzheimer's disease is the most common cause of dementia (Akhondzadeh and Abbasi, 2006) characterised by the build-up in the brain of protein rich plaques and leading to decreased cerebral nerve cell connectivity culminating in the death of nerve cells and loss of brain tissue (Wang et al, 2006a). Associated with decreased acetylcholine (Ach) levels, due to the fact that this is broken down at a higher than average rate by the acetylcholinesterase (AChE). This contributes to incomplete transmission of nerve impulses (Picoulin, 2002). The naturally occurring alkaloid Huperzine A has been shown to be a potent inhibitor of the transport of choline through cholinesterase inhibition resulting in an increase in ACh. AChE inhibition results in a slower rate of breakdown of acetylcholine and in nerve impulses of strength and duration enhancing cerebral performance (Zangara, 2003)
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