Uncovering the Molecular Mechanism of Actions between Pharmaceuticals and Proteins on the AD Network

Abstract

This study begins with constructing the mini metabolic networks (MMNs) of beta amyloid (Aβ) and acetylcholine (ACh) which stimulate the Alzheimer's Disease (AD). Then we generate the AD network by incorporating MMNs of Aβ and ACh, and other MMNs of stimuli of AD. The panel of proteins contains 49 enzymes/receptors on the AD network which have the 3D-structure in PDB. The panel of drugs is formed by 5 AD drugs and 5 AD nutraceutical drugs, and 20 non-AD drugs. All of these complexes formed by these 30 drugs and 49 proteins are transformed into dyadic arrays. Utilizing the prior knowledge learned from the drug panel, we propose a statistical classification (dry-lab). According to the wet-lab for the complex of amiloride and insulin degrading enzyme, and the complex of amiloride and neutral endopeptidase, we are confident that this dry-lab is reliable. As the consequences of the dry-lab, we discover many interesting implications. Especially, we show that possible causes of Tacrine, donepezil, galantamine and huperzine A cannot improve the level of ACh which is against to their original design purpose but they still prevent AD to be worse as Aβ deposition appeared. On the other hand, we recommend Miglitol and Atenolol as the safe and potent drugs to improve the level of ACh before Aβ deposition appearing. Moreover, some nutrients such as NADH and Vitamin E should be controlled because they may harm health if being used in wrong way and wrong time. Anyway, the insights shown in this study are valuable to be developed further.

Fig 1. (A) The general form of MMN of a stimulus. (B) The MMN of Aβ. (C) The MMN of ACh. (D) The MMN of tau protein.

The stimuli (middle products), enzymes, and receptors are highlighted with red, orange, and green colors, respectively.

Fig 2. The AD network generated based on three mini metabolic networks.

For clearly understanding this graph, we state the nodes and edges as follows: enzymes, stimuli, precursors and receptors are the nodes. In which, enzymes are shown by orange ovals, stimuli and their precursors are shown by cyan boxes, and receptors are shown by green ovals. The edges are consisted of three kinds of arrows. In which, green arrows with “+” indicates the up-regulating or activating relationship, while blue arrows with “–” means the down-regulating or inhibiting relationship. The black arrows are the normal up- and down- stream relationship.

Fig 3. The seven areas (H₀- H₆) of complexes to be recommended or rejected.

H₀ is colored with red, H₁ is colored with orange, H₂ is colored with yellow, H₃ is colored with green. H₄ is colored with blue, H₅ is colored with purple, and H₆ is blank.

Fig 4. (A) COX-2 complexes in the NSAIDs only. (B) COX-2 complexes in the NSAIDs and NAI. (C) ACE in complex with the intrinsic ligands only. (D) ACE in complex with the intrinsic ligands and NAI.