DOCSLIB.ORG

Discovery of a Novel Acetylcholinesterase Inhibitor by Fragment-Based Design and Virtual Screening

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Discovery of a Novel Acetylcholinesterase Inhibitor by Fragment-Based Design and Virtual Screening molecules Article Discovery of a Novel Acetylcholinesterase Inhibitor by Fragment-Based Design and Virtual Screening Georgi Stavrakov 1,2,* , Irena Philipova 2, Atanas Lukarski 1, Mariyana Atanasova 1 , Borislav Georgiev 3, Teodora Atanasova 1, Spiro Konstantinov 1 and Irini Doytchinova 1,* 1 Department of Chemistry, Faculty of Pharmacy, Medical University of Sofia, Sofia 1000, Bulgaria; [email protected]fia.bg (A.L.); [email protected]fia.bg (M.A.); [email protected]fia.bg (T.A.); [email protected]fia.bg (S.K.) 2 Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Sofia 1113, Bulgaria; [email protected] 3 Institute of Biodiversity and Ecosystem Research, Bulgarian Academy of Sciences, Sofia 1113, Bulgaria; [email protected] * Correspondence: [email protected]fia.bg (G.S.); [email protected]fia.bg (I.D.) Abstract: Despite extensive and intensive research efforts in recent decades, there is still no effective treatment for neurodegenerative diseases. On this background, the use of drugs inhibiting the enzyme acetylcholinesterase (AChE) remains an eternal evergreen in the symptomatic treatment of mild to moderate cognitive impairments. Even more, the cholinergic hypothesis, somewhat forgotten in recent years due to the shift in focus on amyloid cascade, is back to life, and the search for new, more Citation: Stavrakov, G.; Philipova, I.; effective AChE inhibitors continues. We generated a fragment-based library containing aromatic Lukarski, A.; Atanasova, M.; moieties and linkers originating from a set of novel AChE inhibitors. We used this library to design Georgiev, B.; Atanasova, T.; 1220 galantamine (GAL) derivatives following the model GAL (binding core) - linker (L) - aromatic Konstantinov, S.; Doytchinova, I. fragment (Ar). The newly designed compounds were screened virtually for blood–brain barrier (BBB) Discovery of a Novel permeability and binding to AChE. Among the top 10 best-scored compounds, a representative lead Acetylcholinesterase Inhibitor by molecule was selected and tested for anti-AChE activity and neurotoxicity. It was found that the Fragment-Based Design and Virtual selected compound was a powerful non-toxic AChE inhibitor, 68 times more active than GAL, and Screening. Molecules 2021, 26, 2058. https://doi.org/10.3390/ could serve as a lead molecule for further optimization and development. molecules26072058 Keywords: acetylcholinesterase inhibitor; fragment-based library; molecular docking; BBB perme- Academic Editors: Irena Kostova and ability; galantamine; neurotoxicity; neuro-2A cell line; Ellman’s method Diego Muñoz-Torrero Received: 8 March 2021 Accepted: 31 March 2021 1. Introduction Published: 3 April 2021 Acetylcholinesterase (AChE) is one of the most active enzymes in the central cholin- ergic system [1]. At the cholinergic synapses, it catalyzes the degradation of the neuro- Publisher’s Note: MDPI stays neutral transmitter acetylcholine (ACh) to choline and acetyl and terminates its action on the with regard to jurisdictional claims in postsynaptic ACh receptors. An extensive network of cortical pyramidal neurons, rich in published maps and institutional affil- AChE, has been observed by histochemical analysis of human brains [2]. It has been found iations. that these neurons are absent at birth and during childhood, gradually emerge during adolescence, reach a maximum in early adulthood, and then gradually decrease in the course of normal aging. In patients with neurodegenerative disorders, a severe loss of cholinergic neurons in the cortex and hippocampus is observed due to abnormal accumu- Copyright: © 2021 by the authors. lation of misfolded proteins like amyloid-β (Aβ), τ-protein, α-synuclein [3–7]. This severe Licensee MDPI, Basel, Switzerland. loss is one of the factors responsible for cognitive impairments, typical for Alzheimer’s and This article is an open access article Parkinson’s diseases [8,9]. distributed under the terms and In this regard, the use of drugs able to inhibit the enzyme AChE and hence, to increase conditions of the Creative Commons the levels of ACh in the brain and to improve the cognitive functions has a clear, rational Attribution (CC BY) license (https:// benefit in the treatment of neurodegenerative disorders especially Alzheimer’s disease creativecommons.org/licenses/by/ 4.0/). (AD). Currently, the AChE inhibitors like donepezil, galantamine and rivastigmine, are the Molecules 2021, 26, 2058. https://doi.org/10.3390/molecules26072058 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x 2 of 14 disease (AD). Currently, the AChE inhibitors like donepezil, galantamine and rivastig- Molecules 2021, 26, 2058 mine, are the only FDA- and EMA-approved drugs for the symptomatic treatment2 of 14 of mild to moderate cognitive impairments [10]. The levels of AChE inhibition found in pa- tients treated by current AChE inhibitors are less than the minimum of 50% required for effectiveonly FDA- therapy and EMA-approved of AD [11]. Any drugs attempt for the to symptomatic increase the treatment dose to achieve of mild toa moderatebetter AChE inhibitioncognitive results impairments in an increase [10]. The in levels drug of toxicity AChE and inhibition limits foundthe clinical in patients benefits treated [12]. byThus, thecurrent demand AChE for inhibitors more powerful are less thanand theless minimum toxic AChE of 50% inhibitors required is forstill effective an extremely therapy im- portantof AD [11and]. Anyurgent attempt scientific to increase challenge. the dose to achieve a better AChE inhibition results in anGalantamine increase in drug (GAL) toxicity is one and of the limits most the widely clinical prescribed benefits [12 drug]. Thus,s for the treating demand AD for [13]. Apartmore powerfulfrom being and an less AChE toxic inhibitor, AChE inhibitors GAL is is an still allosteric an extremely modulator important of andnicotinic urgent ACh receptorscientific [14 challenge.], has antioxidant properties [15] and facilitates the clearance of Aβ peptide in rat brainsGalantamine [16]. Due (GAL) to this is onevariety of the of mostactions, widely GAL prescribed can serve drugs as а formultitarget treating ADscaffol [13].d to designApart fromnew derivatives being an AChE with inhibitor, a higher GALAChE is inhibitory an allosteric effect modulator and lower of nicotinictoxicity. AChSteadily inreceptor recent [14decades], has antioxidant, GAL is the properties focus of [15 many] and lab facilitates projects the around clearance the of world Aβ peptide aiming in to developrat brains safer [16 ].and Due more to this powerful variety anti of actions,-neurodegenerative GAL can serve agents as a multitarget [17–27]. scaffold to design new derivatives with a higher AChE inhibitory effect and lower toxicity. Steadily in In the present study, we use GAL as a core structure and design a series of deriva- recent decades, GAL is the focus of many lab projects around the world aiming to develop tives to improve the binding affinity to AChE. Several well-defined domains exist in the safer and more powerful anti-neurodegenerative agents [17–27]. deep Inand the narrow present binding study, we site use of GAL AChE. as aAmong core structure them of and greatest design importance a series of derivatives is the active catalyticto improve site the (CAS), binding consisting affinity of to the AChE. triad Several Ser203 well-defined, Glu334 and domains His447, existand responsible in the deep for ACh'sand narrow hydrolysis binding [28 site]. Along of AChE. the Among binding them gorge of greatest are situated importance the anionic, is the active acyclic, catalytic and ox- yanionsite (CAS), domains. consisting Near of the the triadgorge Ser203, entranc Glu334e is placed and His447, the peripheral and responsible anionic for site ACh’s (PAS), whichhydrolysis is associated [28]. Along with the the binding initiation gorge of areamyloidogenesis situated the anionic, [29]. The acyclic, X-ray and structure oxyanion of the complexdomains. rh NearAChE the-GAL gorge [28 entrance] (Figure is1) placedshows thethat peripheral GAL binds anionic at the sitebottom (PAS), of whichthe binding is siteassociated where withthe CAS the initiation is located of amyloidogenesisand fills only one [29-].third The X-rayof the structure binding ofgorge. the complex The GAL ammoniumrhAChE-GAL group [28] (Figure is pointing1) shows towards that GAL the bindsentrance at the of bottomthe binding of the bindinggorge and site is where the only positionthe CAS in is locatedthe GAL and molecule fills only available one-third for of thesubstitution binding gorge. without The affecting GAL ammonium the binding mode.group is pointing towards the entrance of the binding gorge and is the only position in the GAL molecule available for substitution without affecting the binding mode. FigureFigure 1. 1. XX-ray-ray structure structure of the complexcomplex galantaminegalantamine (GAL)- (GALrh)AChE-rhAChE (pdb (pdb code: code: 4ey6). 4ey6). Protein Protein is is givengiven in in gr grayay ribbon, GAL—inGAL—in ball-and-stickball-and-stick colored colored by by element. element. Our previous structure—AChE affinity studies on GAL derivatives showed that the Our previous structure—AChE affinity studies on GAL derivatives showed that the substitution of CH3 group at the quaternary N-atom with a linker containing five to seven substitution of CH3 group at the quaternary N-atom with a linker containing five to seven carboncarbon atoms atoms and ending
Load more

Recommended publications
  • The Self-Inhibitory Nature of Metabolic Networks and Its Alleviation Through Compartmentalization
    ARTICLE Received 30 Oct 2016 | Accepted 23 May 2017 | Published 10 Jul 2017 DOI: 10.1038/ncomms16018 OPEN The self-inhibitory nature of metabolic networks and its alleviation through compartmentalization Mohammad Tauqeer Alam1,2, Viridiana Olin-Sandoval1,3, Anna Stincone1,w, Markus A. Keller1,4, Aleksej Zelezniak1,5,6, Ben F. Luisi1 & Markus Ralser1,5 Metabolites can inhibit the enzymes that generate them. To explore the general nature of metabolic self-inhibition, we surveyed enzymological data accrued from a century of experimentation and generated a genome-scale enzyme-inhibition network. Enzyme inhibition is often driven by essential metabolites, affects the majority of biochemical processes, and is executed by a structured network whose topological organization is reflecting chemical similarities that exist between metabolites. Most inhibitory interactions are competitive, emerge in the close neighbourhood of the inhibited enzymes, and result from structural similarities between substrate and inhibitors. Structural constraints also explain one-third of allosteric inhibitors, a finding rationalized by crystallographic analysis of allosterically inhibited L-lactate dehydrogenase. Our findings suggest that the primary cause of metabolic enzyme inhibition is not the evolution of regulatory metabolite–enzyme interactions, but a finite structural diversity prevalent within the metabolome. In eukaryotes, compartmentalization minimizes inevitable enzyme inhibition and alleviates constraints that self-inhibition places on metabolism. 1 Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK. 2 Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK. 3 Department of Food Science and Technology, Instituto Nacional de Ciencias Me´dicas y Nutricio´n Salvador Zubira´n, Vasco de Quiroga 15, Tlalpan, 14080 Mexico City, Mexico.
    [Show full text]
  • Plant Protease Inhibitors: a Defense Strategy in Plants
    Biotechnology and Molecular Biology Review Vol. 2 (3), pp. 068-085, August 2007 Available online at http://www.academicjournals.org/BMBR ISSN 1538-2273 © 2007 Academic Journals Standard Review Plant protease inhibitors: a defense strategy in plants Huma Habib and Khalid Majid Fazili* Department of Biotechnology, The University of Kashmir, P/O Naseembagh, Hazratbal, Srinagar -190006, Jammu and Kashmir, India. Accepted 7 July, 2007 Proteases, though essentially indispensable to the maintenance and survival of their host organisms, can be potentially damaging when overexpressed or present in higher concentrations, and their activities need to be correctly regulated. An important means of regulation involves modulation of their activities through interaction with substances, mostly proteins, called protease inhibitors. Some insects and many of the phytopathogenic microorganisms secrete extracellular enzymes and, in particular, enzymes causing proteolytic digestion of proteins, which play important roles in pathogenesis. Plants, however, have also developed mechanisms to fight these pathogenic organisms. One important line of defense that plants have to fight these pathogens is through various inhibitors that act against these proteolytic enzymes. These inhibitors are thus active in endogenous as well as exogenous defense systems. Protease inhibitors active against different mechanistic classes of proteases have been classified into different families on the basis of significant sequence similarities and structural relationships. Specific protease inhibitors are currently being overexpressed in certain transgenic plants to protect them against invaders. The current knowledge about plant protease inhibitors, their structure and their role in plant defense is briefly reviewed. Key words: Proteases, enzymes, protease inhibitors, serpins, cystatins, pathogens, defense. Table of content 1.
    [Show full text]
  • Effect of Statins and ACE Inhibitors Alone and in Combination on Clinical Outcome in Patients with Coronary Heart Disease
    Journal of Human Hypertension (2004) 18, 781–788 & 2004 Nature Publishing Group All rights reserved 0950-9240/04 $30.00 www.nature.com/jhh ORIGINAL ARTICLE Effect of statins and ACE inhibitors alone and in combination on clinical outcome in patients with coronary heart disease VG Athyros1, DP Mikhailidis3, AA Papageorgiou2, VI Bouloukos1, AN Pehlivanidis1, AN Symeonidis4 and M Elisaf5, for the GREACE Study Collaborative Group 1Atherosclerosis Unit, Aristotelian University, Hippocration Hospital, Thessaloniki, Greece; 2Department of Clinical Biochemistry, Royal Free Hospital, Royal Free and University College Medical School, Pond Street, London, UK; 32nd Propedeutic Department of Internal Medicine, Aristotelian University, Hippocration Hospital, Thessaloniki, Greece; 4Greek Society of General Practitioners, Thessaloniki, Greece; 5Department of Internal Medicine, Medical School, University of Ioannina, Greece We assessed the ‘synergy’ of statins and angiotensin- point in group A was 31%, (95% CI À48 to À6%, P ¼ 0.01) converting enzyme inhibitors (ACEI) in reducing vascu- in comparison to group B, 59% (95% CI À72 to À48%, lar events in patients with coronary heart disease (CHD). Po0.0001) to group C and 63% (95% CI À74 to À51%, The GREek Atorvastatin and CHD Evaluation (GREACE) Po0.0001) to group D. There was no significant Study, suggested that aggressive reduction of low difference in RRR between groups C and D (9%, CI density lipoprotein cholesterol to 2.59 mmol/l À27–10%, P ¼ 0.1). Other factors (eg the blood pressure) (o100 mg/dl) significantly reduces morbidity and mor- that can influence clinical outcome did not differ tality in CHD patients, in comparison to undertreated significantly between the four treatment groups.
    [Show full text]
  • Nerve Agent - Lntellipedia Page 1 Of9 Doc ID : 6637155 (U) Nerve Agent
    This document is made available through the declassification efforts and research of John Greenewald, Jr., creator of: The Black Vault The Black Vault is the largest online Freedom of Information Act (FOIA) document clearinghouse in the world. The research efforts here are responsible for the declassification of MILLIONS of pages released by the U.S. Government & Military. Discover the Truth at: http://www.theblackvault.com Nerve Agent - lntellipedia Page 1 of9 Doc ID : 6637155 (U) Nerve Agent UNCLASSIFIED From lntellipedia Nerve Agents (also known as nerve gases, though these chemicals are liquid at room temperature) are a class of phosphorus-containing organic chemicals (organophosphates) that disrupt the mechanism by which nerves transfer messages to organs. The disruption is caused by blocking acetylcholinesterase, an enzyme that normally relaxes the activity of acetylcholine, a neurotransmitter. ...--------- --- -·---- - --- -·-- --- --- Contents • 1 Overview • 2 Biological Effects • 2.1 Mechanism of Action • 2.2 Antidotes • 3 Classes • 3.1 G-Series • 3.2 V-Series • 3.3 Novichok Agents • 3.4 Insecticides • 4 History • 4.1 The Discovery ofNerve Agents • 4.2 The Nazi Mass Production ofTabun • 4.3 Nerve Agents in Nazi Germany • 4.4 The Secret Gets Out • 4.5 Since World War II • 4.6 Ocean Disposal of Chemical Weapons • 5 Popular Culture • 6 References and External Links --------------- ----·-- - Overview As chemical weapons, they are classified as weapons of mass destruction by the United Nations according to UN Resolution 687, and their production and stockpiling was outlawed by the Chemical Weapons Convention of 1993; the Chemical Weapons Convention officially took effect on April 291997. Poisoning by a nerve agent leads to contraction of pupils, profuse salivation, convulsions, involuntary urination and defecation, and eventual death by asphyxiation as control is lost over respiratory muscles.
    [Show full text]
  • A Screening Tool for Acetylcholinesterase Inhibitors
    RESEARCH ARTICLE Comparative biophysical characterization: A screening tool for acetylcholinesterase inhibitors 1 1 2 1 Devashree N. Patil , Sushama A. Patil , Srinivas SistlaID , Jyoti P. JadhavID * 1 Department of Biotechnology, Shivaji University, Kolhapur, MS, India, 2 Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, Virginia, United States * [email protected] a1111111111 a1111111111 a1111111111 a1111111111 Abstract a1111111111 Among neurodegenerative diseases, Alzheimer's disease (AD) is one of the most grievous disease. The oldest cholinergic hypothesis is used to elevate the level of cognitive impairment and acetylcholinesterase (AChE) comprises the major targeted enzyme in AD. Thus, acetylcholinesterase inhibitors (AChEI) constitutes the essential remedy for the treat- OPEN ACCESS ment of AD. The study aims to evaluate the interactions between natural molecules and Citation: Patil DN, Patil SA, Sistla S, Jadhav JP AChE by Surface Plasmon Resonance (SPR). The molecules like alkaloids, polyphenols (2019) Comparative biophysical characterization: A screening tool for acetylcholinesterase inhibitors. and substrates of AChE have been considered for the study with a major emphasis on affin- PLoS ONE 14(5): e0215291. https://doi.org/ ity and kinetics. To better understand the activity of small molecules, the investigation is sup- 10.1371/journal.pone.0215291 ported by both experimental and theoretical approach such as fluorescence, Circular Editor: David A. Lightfoot, College of Agricultural Dichroism (CD) and molecular docking studies. Amongst the screened ones tannic acid Sciences, UNITED STATES showed promising results compared with others. The methodology followed here have Received: September 26, 2018 highlighted many molecules with a higher affinity towards AChE and these findings may Accepted: March 30, 2019 take lead molecules generated in preclinical studies to treat neurodegenerative diseases.
    [Show full text]
  • Acetylcholinesterase — New Roles for Gate a Relatively Long Distance to Reach the Active Site, Ache Is One of the Fastest an Old Actor Enzymes14
    PERSPECTIVES be answered regarding AChE catalysis; for OPINION example, the mechanism behind the extremely fast turnover rate of the enzyme. Despite the fact that the substrate has to navi- Acetylcholinesterase — new roles for gate a relatively long distance to reach the active site, AChE is one of the fastest an old actor enzymes14. One theory to explain this phe- nomenon has to do with the unusually strong electric field of AChE. It has been argued that Hermona Soreq and Shlomo Seidman this field assists catalysis by attracting the cationic substrate and expelling the anionic The discovery of the first neurotransmitter — understanding of AChE functions beyond the acetate product15. Site-directed mutagenesis, acetylcholine — was soon followed by the classical view and suggest the molecular basis however, has indicated that reducing the elec- discovery of its hydrolysing enzyme, for its functional heterogeneity. tric field has no effect on catalysis16.However, acetylcholinesterase. The role of the same approach has indicated an effect on acetylcholinesterase in terminating From early to recent discoveries the rate of association of fasciculin, a peptide acetylcholine-mediated neurotransmission The unique biochemical properties and phys- that can inhibit AChE17. made it the focus of intense research for iological significance of AChE make it an much of the past century. But the complexity interesting target for detailed structure–func- of acetylcholinesterase gene regulation and tion analysis. AChE-coding sequences have recent evidence for some of the long- been cloned so far from a range of evolution- a Peripheral Choline binding site suspected ‘non-classical’ actions of this arily diverse vertebrate and invertebrate binding enzyme have more recently driven a species that include insects, nematodes, fish, site profound revolution in acetylcholinesterase reptiles, birds and several mammals, among Active site research.
    [Show full text]
  • Skeletal Muscles in Chick Embryo (Cholinergic Receptor/Choline Acetyltransferase/Acetylcholinesterase/ Embryonic Development of Neuromuscular Junction) G
    Proc. Nat. Acad. Sci. USA Vol. 70, No. 6, pp. 1708-1712, June 1973 Effects of a Snake a-Neurotoxin on the Development of Innervated Skeletal Muscles in Chick Embryo (cholinergic receptor/choline acetyltransferase/acetylcholinesterase/ embryonic development of neuromuscular junction) G. GIACOBINI, G. FILOGAMO, M. WEBER, P. BOQUET, AND J. P. CHANGEUX Department of Human Anatomy, University of Turin, Turin, Italy; and Department of Molecular Biology, Institut Pasteur, Paris, France Communicated by Frankois Jacob, March 15, 1973 ABSTRACT The evolution of the cholinergic (nicotinic) The embryos were treated with a-toxin by three successive receptor in chick muscles is monitored during embryonic injections (the 3rd, 8th, and 12th day of incubation) in the yolk development with a tritiated a-neurotoxin from Naja nigri- collis and compared with the appearance of acetylcholines- sac with a Hamilton syringe, through a small window in the terase. The specific activity of these two proteins reaches a shell. Each time, 20-100 Al of a 1 mg/ml solution in sterile maximum around the 12th day of incubation. By contrast, Ringer's solution was injected. Embryos were examined the choline acetyltransferase reaches an early maximum of 16th day of incubation. About 30% of the injected embryos specific activity around the 7th day of development, and later continuously increases until hatching. Injection of died during development. a-toxin in the yolk sac at early stages ofdevelopment causes Homogenization. The tissue was added to ice-cold Ringer's an atrophy of skeletal and extrinsic ocular-muscles solution (for [3H ]a-toxin binding), to 0.5%O Triton X-100 in and of their innervation.
    [Show full text]
  • 388Fc33bdf5b91affd8650f371de
    molecules Article In Vitro and In Silico Acetylcholinesterase Inhibitory Activity of Thalictricavine and Canadine and Their Predicted Penetration across the Blood-Brain Barrier Jakub Chlebek 1,* , Jan Korábeˇcný 2,3 , Rafael Doležal 2,4,Šárka Štˇepánková 5, Daniel I. Pérez 6, Anna Hošt’álková 1 , Lubomír Opletal 1, Lucie Cahlíková 1, KateˇrinaMacáková 1, Tomáš Kuˇcera 3 , Martina Hrabinová 2,3 and Daniel Jun 2,3 1 ADINACO Research Group, Department of Pharmaceutical Botany, Faculty of Pharmacy, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic; [email protected] (A.H.); [email protected] (L.O.); [email protected] (L.C.); [email protected] (K.M.) 2 Biomedical Research Center, University Hospital Hradec Králové, Sokolská 581, 500 05 Hradec Králové, Czech Republic; [email protected] (J.K.); [email protected] (R.D.); [email protected] (M.H.); [email protected] (D.J.) 3 Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defense, Tˇrebešská 1575, 500 01 Hradec Králové, Czech Republic; [email protected] 4 Center for Basic and Applied Research, Faculty of Informatics and Management, University of Hradec Králové, Rokitanského 62, 50003 Hradec Králové, Czech Republic 5 Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentská 95, 532 10 Pardubice, Czech Republic; [email protected] 6 Centro de Investigaciones Biológicas, Avenida Ramiro de Maetzu 9, 280 40 Madrid, Spain; [email protected] * Correspondence: [email protected]; Tel.: +420-495067232; Fax: +420-495067162 Academic Editor: Derek J.
    [Show full text]
  • Kinase-Targeted Cancer Therapies: Progress, Challenges and Future Directions Khushwant S
    Bhullar et al. Molecular Cancer (2018) 17:48 https://doi.org/10.1186/s12943-018-0804-2 REVIEW Open Access Kinase-targeted cancer therapies: progress, challenges and future directions Khushwant S. Bhullar1, Naiara Orrego Lagarón2, Eileen M. McGowan3, Indu Parmar4, Amitabh Jha5, Basil P. Hubbard1 and H. P. Vasantha Rupasinghe6,7* Abstract The human genome encodes 538 protein kinases that transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are associated with human cancer initiation and progression. The recent development of small-molecule kinase inhibitors for the treatment of diverse types of cancer has proven successful in clinical therapy. Significantly, protein kinases are the second most targeted group of drug targets, after the G-protein- coupled receptors. Since the development of the first protein kinase inhibitor, in the early 1980s, 37 kinase inhibitors have received FDA approval for treatment of malignancies such as breast and lung cancer. Furthermore, about 150 kinase-targeted drugs are in clinical phase trials, and many kinase-specific inhibitors are in the preclinical stage of drug development. Nevertheless, many factors confound the clinical efficacy of these molecules. Specific tumor genetics, tumor microenvironment, drug resistance, and pharmacogenomics determine how useful a compound will be in the treatment of a given cancer. This review provides an overview of kinase-targeted drug discovery and development in relation to oncology and highlights the challenges and future potential for kinase-targeted cancer therapies. Keywords: Kinases, Kinase inhibition, Small-molecule drugs, Cancer, Oncology Background Recent advances in our understanding of the fundamen- Kinases are enzymes that transfer a phosphate group to a tal molecular mechanisms underlying cancer cell signaling protein while phosphatases remove a phosphate group have elucidated a crucial role for kinases in the carcino- from protein.
    [Show full text]
  • Acetylcholinesterase-Transgenic Mice Display Embryonic Modulations In
    Proc. Natl. Acad. Sci. USA Vol. 94, pp. 8173–8178, July 1997 Neurobiology Acetylcholinesterase-transgenic mice display embryonic modulations in spinal cord choline acetyltransferase and neurexin Ib gene expression followed by late-onset neuromotor deterioration (neuromuscular junctionymotoneurons) CHRISTIAN ANDRES*†‡,RACHEL BEERI*‡,ALON FRIEDMAN*, EFRAT LEV-LEHMAN*, SIVAN HENIS*, RINA TIMBERG*, MOSHE SHANI§, AND HERMONA SOREQ*¶ *Department of Biological Chemistry, The Hebrew University of Jerusalem, 91904 Israel; and §Department of Molecular Genetics, Agricultural Research Organization, The Volcani Center, Bet Dagan, 50250 Israel Communicated by Roger D. Kornberg, Stanford University School of Medicine, Stanford, CA, May 9, 1997 (received for review March 12, 1997) ABSTRACT To explore the possibility that overproduc- like domain of neurotactin was replaced with the homologous tion of neuronal acetylcholinesterase (AChE) confers changes domain from Torpedo AChE was reported to retain ligand- in both cholinergic and morphogenic intercellular interac- dependent cell-adhesive properties similar to the native mol- tions, we studied developmental responses to neuronal AChE ecule (10). This reinforced the notion that AChE may play a overexpression in motoneurons and neuromuscular junctions role in neuronal cell adhesion. of AChE-transgenic mice. Perikarya of spinal cord motoneu- In mammals, the AChE-homologous neuroligins were iden- rons were consistently enlarged from embryonic through tified as heterophilic ligands for a splice-site specific form of adult stages in AChE-transgenic mice. Atypical motoneuron the synapse-enriched neuronal cell surface protein neurexin Ib development was accompanied by premature enhancement in (11). Neurexins represent a family of three homologous genes the embryonic spinal cord expression of choline acetyltrans- (I, II, and III), giving rise to a and b forms that can undergo ferase mRNA, encoding the acetylcholine-synthesizing enzyme further alternative splicing to generate over 1,000 isoforms choline acetyltransferase.
    [Show full text]
  • Identification of Novel Monoamine Oxidase B Inhibitors from Ligand Based Virtual Screening
    Identification of novel monoamine oxidase B inhibitors from ligand based virtual screening A thesis submitted to Kent State University in partial Fulfillment of the requirements for the Degree of Master of Science By Mohammed Alaasam August, 2014 Thesis written by Mohammed Alaasam B.S., University of Baghdad, 2007 M.S., Kent State University, 2014 Approved by Werner Geldenhuys , Chair, Master’s Thesis Committee Richard Carroll , Member, Master’s Thesis Committee Prabodh Sadana , Member, Master’s Thesis Committee Eric Mintz , Director, School of Biomedical Sciences James Blank , Dean, College of Arts and Sciences ii Table of Contents List of figure ...................................................................................................................... vi List of tables ..................................................................................................................... xiii Acknowledgments............................................................................................................ xiv Chapter one: Introduction ............................................................................................... 1 1.1.Parkinson's disease ....................................................................................................... 1 1.2.Monoamine oxidase enzymes ....................................................................................... 7 1.3.Structures of MAO enzymes ....................................................................................... 12 1.4.Three dimentiona
    [Show full text]
  • Human Erythrocyte Acetylcholinesterase
    Pediat. Res. 7: 204-214 (1973) A Review: Human Erythrocyte Acetylcholinesterase FRITZ HERZ[I241 AND EUGENE KAPLAN Departments of Pediatrics, Sinai Hospital, and the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Introduction that this enzyme was an esterase, hence the term "choline esterase" was coined [100]. Further studies In recent years the erythrocyte membrane has received established that more than one type of cholinesterase considerable attention by many investigators. Numer- occurs in the animal body, differing in substrate ous reviews on the composition [21, 111], immunologic specificity and in other properties. Alles and Hawes [85, 116] and rheologic [65] properties, permeability [1] compared the cholinesterase of human erythro- [73], active transport [99], and molecular organiza- cytes with that of human serum and found that, tion [109, 113, 117], attest to this interest. Although although both enzymes hydrolyzed acetyl-a-methyl- many studies relating to membrane enzymes have ap- choline, only the erythrocyte cholinesterase could peared, systematic reviews of this area are limited. hydrolyze acetyl-yg-methylcholine and the two dia- More than a dozen enzymes have been recognized in stereomeric acetyl-«: /3-dimethylcholines. These dif- the membrane of the human erythrocyte, although ferences have been used to delineate the two main changes in activity associated with pathologic condi- types of cholinesterase: (1) acetylcholinesterase, or true, tions are found regularly only with acetylcholinesterase specific, E-type cholinesterase (acetylcholine acetyl- (EC. 3.1.1.7). Although the physiologic functions of hydrolase, EC. 3.1.1.7) and (2) cholinesterase or erythrocyte acetylcholinesterase remain obscure, the pseudo, nonspecific, s-type cholinesterase (acylcholine location of this enzyme at or near the cell surface gives acylhydrolase, EC.
    [Show full text]