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Current Acetylcholinesterase-Inhibitors: a Neuroinformatics Perspective

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Current Acetylcholinesterase-Inhibitors: a Neuroinformatics Perspective Send Orders for Reprints to [email protected] CNS & Neurological Disorders - Drug Targets, 2014, 13, 391-401 391 Current Acetylcholinesterase-Inhibitors: A Neuroinformatics Perspective Sibhghatulla Shaikh1,†, Anupriya Verma2,†, Saimeen Siddiqui1,†, Syed Sayeed Ahmad2, Syed Mohd. Danish Rizvi1, Shazi Shakil*,2, Deboshree Biswas1, Divya Singh1, Mohd. Haris Siddiqui2, Shahnawaz Shakil3, Shams Tabrez4 and Mohammad Amjad Kamal4 1Department of Biosciences, Integral University, Lucknow-226026, India 2Department of Bio-Engineering, Integral University, Lucknow-226026, India 3Cardinal Health 7000, Cardinal Place, Dublin OH 43017, USA 4King Fahd Medical Research Centre, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia Abstract: This review presents a concise update on the inhibitors of the neuroenzyme, acetylcholinesterase (AChE; EC 3.1.1.7). AChE is a serine protease, which hydrolyses the neurotransmitter, acetylcholine into acetate and choline thereby terminating neurotransmission. Molecular interactions (mode of binding to the target enzyme), clinical applications and limitations have been summarized for each of the inhibitors discussed. Traditional inhibitors (e.g. physostigmine, tacrine, donepezil, rivastigmine etc.) as well as novel inhibitors like various physostigmine-derivatives have been covered. This is followed by a short glimpse on inhibitors derived from nature (e.g. Huperzine A and B, Galangin). Also, a discussion on ‘hybrid of pre-existing drugs’ has been incorporated. Furthermore, current status of therapeutic applications of AChE- inhibitors has also been summarized. Keywords: Acetylcholinesterase, acetylcholine, physostigmine, rivastigmine, huperzine A. 1. INTRODUCTION gravis (MG) [5], Parkinson’s disease (PD) [6] and other ‘non-classical’ activities such as cell adhesion, neurite The Nobel Prize in Physiology or Medicine 1936 was formation and network formation [7] elicited numerous shared by Sir Henry Hallett Dale and Otto Loewi for their researches relevant to the medical field. findings with reference to chemical transmission of nerve impulses. Until 1921 it was believed that the transmission of nerve impulses was ‘electrical’ in nature. But this theory was not acceptable due to two reasons, one being the presence of gap between neurons and effecter organs and the other a Fig. (1). Reaction catalyzed by AChE. The enzyme hydrolyses ACh decrease in activity due to impulses from inhibitory nerves. into acetate and choline (Source: Hay, D et al. 2010 [9]). Otto Loewi proved the ‘Chemical’ nature of impulse transmission through his famous experiment of two beating 2. STRUCTURE OF ACETYLCHOLINESTERASE hearts from frogs – one connected to vagus nerve and AChE (EC 3.1.1.7) is one of the two cholinesterases, accelerator nerves; second one without any nerve more specifically a serine protease, which hydrolyses ACh connection. In this experiment he discovered the first neurotransmitter into acetate and choline and hence, neurotransmitter ‘acetylcholine’ (ACh) [1]. ACh is a neurotransmitter widely distributed in the central (and also terminates neurotransmission. Due to the presence of a common α/β fold, it is included in the α/β fold super family, peripheral, autonomic and enteric) nervous system (CNS). In works near its diffusion control rate [8] and possesses a high the CNS, ACh facilitates many functions, such as learning, ‘turn-over rate’ of 2.5x104 ACh molecules per second. memory, attention and motor control. In 1914, Sir Henry Dale suggested that an enzyme which degrades the esters of It is revealed by its crystal structure that the catalytic choline, played a role in neurotransmission within the triad, formed by serine, histidine and glutamate, is present at autonomic and somatic motor nervous systems and that this the bottom of a narrow gorge of about 20-A° size. This gorge enzyme, acetylcholinesterase (AChE), was the target of widens at the base. Catalytic triad (S200, E327 and H440 in action of the drug, physostigmine (eserine) [2]. Hence, case of Torpedo californica) is designated to ‘esteratic site’ AChE enzyme regulated the release and entry of ACh in or ‘acylation site’ or ‘A-site’. A planar array formed by these cholinergic fibers [3]. Role of AChE in neurological three residues closely resembles the catalytic triad of disorders like Alzheimer’s disease (AD) [4], Myasthenia chymotrypsin and of other serine proteases except that the glutamate is the third member rather than the asparate [9, 10]. Serine is responsible for hydrolysis of choline esters *Address correspondence to this author at the Department of Bio-engineering, through proton transfer in catalytic triad. Cationic-π site Integral University, Lucknow, 226026, India; Tel: +91-8004702899; Fax: (CAS) is present above esteratic site, where quaternary +91-522-2890809; E-mail: [email protected] ammonium of choline of ACh interacts. CAS is followed by †Equally contributing authors. PAS (Peripheral Anionic Site) or P-site which forms mouth 1871-5273/14 $58.00+.00 © 2014 Bentham Science Publishers 392 CNS & Neurological Disorders - Drug Targets, 2014, Vol. 13, No. 3 Shaikh et al. of the gorge [11]. Anciently, it was believed that PAS The molecular forms of AChE correspond to various comprises of several negatively charged amino acids due to quaternary structures and modes of anchoring of the enzyme. its preference to bind cationic ligands. However, the These forms are determined by alternate splicing of AChE gene. hypothesis was discarded [12]. The high aromatic content of AChE variants are produced by alternate splicing, each with a the deep and narrow active-site gorge of AChE is a different carboxy-terminal sequence. These carboxy-terminal remarkable feature of this enzyme. There are 14 conserved sequences determine their homologous assembly into AChE aromatic amino acids lined along the gorge of Torpedo oligomers and their heterologous association with non-catalytic californica AChE (TcAChE), namely F120, F288, F290, subunits that direct the subcellular localization of the protein. F330, F331, W84, W233, W279, W432, Y70, Y121, Y130, The three AChE variants are – the ‘synaptic’ (S) or ‘tailed’ (T), Y334, and Y442 [12]. Tryptophan 84 is critical among all ‘erythrocytic’ (E) or ‘hydrophobic’ (H) and ‘readthrough’ (R) the aromatic amino acids and its substitution with alanine AChE isoforms. AChE-S is the only type of catalytic subunit results in a 3000-fold decrease in reactivity [13]. Beside that exists in all vertebrate cholinesterases. It produces the major these sites, AChE possesses ‘Acyl pocket’ which confers forms in adult brain and muscle. In AChE-E, a glycyl bond near substrate specificity and ‘Oxyanion Hole’ which the carboxyl terminus undergoes transamidation to attach a accommodates negative oxygen ion during catalysis for glycophosphatidylinositol group to the protein, which anchors catalytic efficiency of the enzyme [14]. the mature AChE-E to the outer surface of erythrocytes. AChE- R doesn’t acquire any feature for attachment and hence, remain monomeric (G1) and soluble [15-18]. Fig. (2). Schematic view of the active-site gorge of TcAChE 2.1. Targeting AChE [Source: Hay, D et al. 2010 [9]. The inhibitors of AChE help in increasing the concentration and duration of action of acetylcholine by resisting the breakdown of ACh. Many of these inhibitors are constituted in prescription for many neurological diseases such as AD etc. Although the inhibition is needed but, ''total'' inhibition of AChE causes ‘toxicity’. Thus, AChEIs can be classified into reversible, quasi-irreversible and irreversible inhibitors on the basis of affinity of AChEIs toward AChE. Reversible inhibitors act till their concentration is sufficient and are transient in nature. Irreversible and quasi-irreversible inhibitors form covalent bonds with the enzyme and inhibit it irreversibly. Such inhibitors are rarely used as therapeutics and are mainly used as insecticides/pesticides and chemical warfare agents (nerve gases). 2.2. Traditional AChE Inhibitors 2.2.1. Physostigmine (Eserine) The IUPAC name of Physostigmine (Eserine) is (3aR, Fig. (3). Recombinant human AChE [PDB id: 3LII]. 8aS)-1,3a,8-Trimethyl-1H, 2H, 3H, 3aH, 8H, 8aH-pyrrolo[2, Fig. (4). Alternative splicing and molecular forms of AChE (Source: Massoulié, J et al. 1999 [16]). Current Acetylcholinesterase-Inhibitors CNS & Neurological Disorders - Drug Targets, 2014, Vol. 13, No. 3 393 3-b]indol-5-ylN-methylcarbamate. It was the first choli- (a) nesterase inhibitor that was investigated for AD. It is an alkaloid usually obtained from dried ripe seeds of Physostigma venenosum (Calabar bean) and gives primarily muscarinic effects. It also possesses capability to cross the blood-brain barrier but has a short half-life and narrow therapeutic index. Moreover, there are many side effects such as nausea, vomiting, diarrhea, headaches and dizziness associated with the drug. This drug was in use for MG, delayed gastric emptying and glaucoma. However, it was not approved for AD. (b) Fig. (5). Chemical structure of Physostigmine. 2.2.2. Tacrine The IUPAC name of tacrine is 1, 2, 3, 4- tetrahydroacridin-9-amine. In 1993 tacrine was approved for AD. Tacrine is a potent inhibitor of both AChE and butyrylcholinesterase (BuChE). It is a synthetic ChEI. It has limited clinical applications due to hepatotoxicity via elevation of serum alanine aminotransferase levels. It is also associated with side effects such as nausea, vomiting, dizziness, diarrhoea, seizures, and syncope. A research shows
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