Computational Determination of the Affinity and Binding Efficiency of Non-Steroidal Anti-Inflammatory Drugs Cyclooxygenase-2 Inhibitors
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Abstract
A computational study of the interaction of nonsteroidal antiinflammatory drugs with Cyclooxygenase 2 (COX-2) enzyme is shown. The objective was to determine the affinity of the inhibitors studied with the active site of the enzyme and calculate their binding efficiency. Furthermore, it is intended to check the applicability of the methods of molecular docking in determining promising molecules in order to accelerate drug discovery research. Molecular dynamics methods, using Autodock VINA, were used to model the interactions between the COX-2 enzyme with celecoxib, diclofenac, etoricoxib, indomethacin, ibuprofen, naproxen, and meloxicam. Results show that the molecule with higher affinity for COX-2 is celecoxib with a binding energy of -10.8 kcal/mol and an equilibrium constant Ki of 1.21x10-8 M. Ibuprofen and naproxen are the molecules with higher binding efficiency with a values greater than -0.48 kcal/mol/ atoms (other than hydrogen). This shows that a molecule having a good affinity, not necessarily will have a good binding efficiency. These values give researchers a guideline to choose the best molecule to inhibit COX-2 enzyme and in cases of drug discovery processes, the ideal molecule to invest in their improvement and optimization to make it an approved drug.
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Meneses L, Cuesta S. Computational Determination of the Affinity and Binding Efficiency of Non-Steroidal Anti-Inflammatory Drugs Cyclooxygenase-2 Inhibitors. REMCB [Internet]. 2017Aug.15 [cited 2024Jul.3];36(1-2):17-5. Available from: https://remcb-puce.edu.ec/remcb/article/view/260
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Artículos Científicos
References
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Abdel-Azeem A, Abdel-Hafez A, El-Karamany G y Farag H. 2009. Chlorzoxazone esters of some non-steroidal anti-infllammatory (NSAI) carboxylic acids as mutual prodrugs: Design, synthesis, pharmacological investigations and docking studies. Bioorganic & Medicinal Chemistry, 17: 3665–3670.
American Society of Health-System Pharmacists. 2015. Consumer Medication Information. Página de Internet: http://www.nlm.nih. gov/medlineplus/spanish/druginfo/meds/ a689002-es.html Consultada 06-junio-2015.
Atkinson A y Abernethy D. 2007. Principles of Clinical Pharmacology. Segunda edición. Elsevier Inc. UK. 146-149 pp.
Berman H, Westbrook J, Feng Z, Gilliland G, Bath T, Weissig H, Shindyalov I and Bournel P. 2000. The Protein Data Bank, Oxford Journals Nucleic Acids Research, 28 (1): 235-242.
Blobaum A y Marnett L. 2007. Structural and Functional Basis of Cyclooxygenase Inhibition, Journal of Medicinal Chemistry, 50 (7): 1425-1441.
Brunton L y Parker K. 2008. Goodman & Gilman’s Manual of Pharmacology and Therapeutics. Décimo primera edición. McGraw-Hill. USA. 421, 428, 429, 436, 451 pp.
Davies NM y Skjodt NM. 2000. Choosing the right nonsteroidal anti-inflammatory drug for the right patient: a pharmacokinetic approach, Clinical Pharmacokinetics, 38 (5): 377-392.
DeWitt D. 1999. Cox-2-Selective Inhibitors: The New Super Aspirins, Molecular Pharmacology, 55: 625–631.
Ermondi G, Caron G, Lawrence R y Longo D. 2004. Docking studies on NSAID/COX-2 isozyme complexes using Contact Statistics analysis. Journal of Computer-Aided Molecular Design, 18: 683–696.
Graham P. 2001. An Introduction to Medicinal Chemistry. Quinta edición. Oxford. Reino Unido. 116, 211 pp.
Griffin M. 2015. Pain Relief: How NSAIDs Work. Página de Internet: http://www.webmd.com/ arthritis/features/pain-relief-how-nsaids-work Consultada 03-Junio-2015.
Hall V, Murillo N, Rocha M y Rodríguez E. 2001. Antinflamatorios No Esteroidales. Centro Nacional de Información de Medicamentos, Instituto de Investigaciones Farmacéuticas. Universidad de Costa Rica, Costa Rica. 7: 13,14 pp.
Hopkins A, Keserű G, Leeson P, Rees P y Reynolds C. 2014. The Role of Ligand Efficiency Measures in Drug Discovery, Nature reviews drug discovery, 13 (2): 105-121.
Kitchen D, Decornez H, Furr J y Bajorath J. 2004. Docking and scoring in virtual screening for drug discovery: methods and applications. Nature reviews: Drug discovery, 3: 935-949.
McMurry, J. 2004. Organic Chemistry, sexta edición. Thomson, USA. 305, 519, 1034, 1035 pp.
Murray C, Erlanson D, Hopkins A, Keseru G, Leeson P, Rees D, Reynolds C y Richmond N. 2014. Validity of Ligand Efficiency Metrics, ACS Medicinal Chemistry Letters, 5: 616-618.
Murray R, Granner D, Mayes P y Rodwell V. 2003. Harper’s Illustrated Biochemistry. Vigésima sexta edición. McGraw-Hill. USA. 49, 50, 190-194 pp.
Nelson D y Cox M. 2008. Lehninger Principles of Biochemistry. Quinta edición. W.H Freeman and Company. USA. 184, 358, 817, 1184 pp.
Pettersen E, Goddard T, Huang C, Couch G, Greenblatt D, Meng E y Ferrin T. 2004. UCSF Quimera - a visualization system for exploratory research and analysis. Journal of Computational Chemistry, 25 (13): 1605-1612.
Pouplana R, Lozano J y Ruiz J. 2002. Molecular modelling of the differential interaction between several non-steroidal anti-infllammatory drugs and human prostaglandin endoperoxide H synthase-2 (h-PGHS-2). Journal of Molecular Graphics and Modelling, 20: 329–343.
Reynolds C, Tounge B y Bembenek S. 2008. Ligand Binding Effiiciency: Trends, Physical Basis, and Implications J. Med. Chem, 51: 2432–2438.
Reynolds C y Holloway M. 2011. Thermodynamics of Ligand Binding and Efficiency, ACS Medicinal Chemistry Letters, 2: 433-437.
Savic J, Dilber S, Markovic B, Milenkovic M, Vladimirov S y Juranic I. 2011. Docking Studies and a-Substitution Effects on the Anti-Inflammatory Activity of ß-Hydroxy-ß-arylpropanoic Acids. Molecules, 16: 6645-6655.
Standford Medicine. 2005. Pain Research at Stanford. Página de Internet: http://med.stanford.edu/paincenter/research.html. Consultada 03-junio-2015.
Stevens E. 2012. Medicinal Chemistry: The Modern Drug Discovery Process. Primera edición. Pearson. USA. 106, 254 pp.
Stevens E. 2014. 001 x: Medicinal Chemistry: The molecular basis of drug discovery, a course of study offered by Davidson College through edX platform, disponible en www.edx.org, chapters 4,1; 4,3; 9,1; 10,2. Consultada 11-febrero-2015.
The Scripps Research Institute. 2013. Autodock. Página de Internet: http://autodock.scripps.edu/, 24/09/2013 Consultada 03-junio-2015