Effects of 4-Ethyl Resorcinol and 5-Methylresorcinol on Human Carbonic Anhydrase-I and Molecular Docking Study

Öz

Carbonic Anhydrase-I (CA-I) is the most abundant CA isozyme expressed in human erythrocytes and the gastrointestinal (GI) tract. CA-I acts in promoting biocalcification. It is well known that inhibitors of carbonic anhydrase (CAIs) are widely used in the remedy of some diseases such as edema, glaucoma, idiopathic intracranial hypertension, and osteoporosis. So, in this study, it was aimed to analyze primer effects of 4-ethylresorcinol and 5-methylresorcinol on hCA-I and to clarify inhibition profiles of compounds. For this purpose, firstly hCA-I was isolated from human erythrocytes by affinity chromatography. Secondly, in vitro inhibition studies were performed and interactions between compounds and enzyme were explained via molecular docking study. Both 4-ethylresorcinol and 5-methylresorcinol inhibited the enzyme competitively with Ki constant of 0.81±0.23 and 0.79±0.14 μM. According to molecular docking analysis estimated free energy of binding of compounds were predicted as -4.81 and -4.51 kcal.mol-1 respectively.

Anahtar Kelimeler

• Binding energy
• carbonic anhydrase-1
• inhibition
• in vitro
• molecular docking
• resorcinol

Kaynakça

1. Adem S, Akkemik E, Aksit H, Guller P, Tufekci AR, Demirtas I, Ciftci M, 2019. Activation and Inhibition Effects of Some Natural Products on Human Cytosolic Cai and Caii. Medicinal Chemistry Research 28(5): 711-722.
2. Aggarwal M, McKenna R, 2012. Update on Carbonic Anhydrase Inhibitors: A Patent Review (2008-2011). Expert Opinion on Therapeutic Patents 22(8): 903-915.
3. Ahlskog JKJ, Dumelin CE, Trussel S, Marlind J, Neri D, 2009. In Vivo Targeting of Tumor-Associated Carbonic Anhydrases Using Acetazolamide Derivatives. Bioorganic & Medicinal Chemistry Letters 19(16): 4851-4856.
4. Alterio V, Di Fiore A, D'Ambrosio K, Supuran CT, De Simone G, 2012. Multiple Binding Modes of Inhibitors to Carbonic Anhydrases: How to Design Specific Drugs Targeting 15 Different Isoforms? Chemical Reviews 112(8): 4421-4468.
5. Alterio V, Monti SM, Truppo E, Pedone C, Supuran CT, De Simone G, 2010. The First Example of a Significant Active Site Conformational Rearrangement in a Carbonic Anhydrase-Inhibitor Adduct: The Carbonic Anhydrase I-Topiramate Complex. Organic & Biomolecular Chemistry 8(15): 3528-3533.
6. Alyar S, Adem S, 2014. Synthesis, Characterization, Antimicrobial Activity and Carbonic Anhydrase Enzyme Inhibitor Effects of Salicilaldehyde-N-Methyl P-Toluenesulfonylhydrazone and Its Palladium(Ii), Cobalt(Ii) Complexes. Spectrochimica Acta Part a-Molecular and Biomolecular Spectroscopy 131: 294-302.
7. Alyar S, Sen CH, Alyar H, Adem S, Kalkanci A, Ozdemir UO, 2018. Synthesis, Characterization, Antimicrobial Activity, Carbonic Anhydrase Enzyme Inhibitor Effects, and Computational Studies on New Schiff Bases of Sulfa Drugs and Their Pd(Ii), Cu(Ii) Complexes. Journal of Molecular Structure 1171: 214-222.
8. Argan O, Cikrikci K, Baltaci A, Gencer N, 2020. The Effects of Cardiac Drugs on Human Erythrocyte Carbonic Anhydrase I and Ii Isozymes. J Enzyme Inhib Med Chem 35(1): 1359-1362.

9. Arslan T, Ceylan MB, Bas H, Biyiklioglu Z, Senturk M, 2020. Design, Synthesis, Characterization of Peripherally Tetra-Pyridine-Triazole-Substituted Phthalocyanines and Their Inhibitory Effects on Cholinesterases (Ache/Bche) and Carbonic Anhydrases (Hca I, Ii and Ix). Dalton Transactions 49(1): 203-209.
10. Arslan T, Turkoglu EA, Senturk M, Supuran CT, 2016. Synthesis and Carbonic Anhydrase Inhibitory Properties of Novel Chalcone Substituted Benzenesulfonamides. Bioorganic & Medicinal Chemistry Letters 26(24): 5867-5870.
11. Chang XT, Zheng YB, Yang QR, Wang L, Pan JH, Xia YF, Yan XF, Han JX, 2012. Carbonic Anhydrase I (Ca1) Is Involved in the Process of Bone Formation and Is Susceptible to Ankylosing Spondylitis. Arthritis Research & Therapy 14(4).
12. D'Ambrosio K, Carradori S, Monti SM, Buonanno M, Secci D, Vullo D, Supuran CT, De Simone G, 2015. Out of the Active Site Binding Pocket for Carbonic Anhydrase Inhibitors. Chemical Communications 51(2): 302-305.
13. Durairaj RB, 2005. Resorcinol : Chemistry, Technology, and Applications. Berlin ; New York, Springer.
14. Ekinci D, Beydemir S, Kufrevioglu OI, 2007. In Vitro Inhibitory Effects of Some Heavy Metals on Human Erythrocyte Carbonic Anhydrases. Journal of Enzyme Inhibition and Medicinal Chemistry 22(6): 745-750.
15. Esirden I, Ulus R, Aday B, Tanc M, Supuran CT, Kaya M, 2015. Synthesis of Novel Acridine Bis-Sulfonamides with Effective Inhibitory Activity against the Carbonic Anhydrase Isoforms I, Ii, Ix and Xii. Bioorganic & Medicinal Chemistry 23(20): 6573-6580.
16. Gulcin I, Scozzafava A, Supuran CT, Akincioglu H, Koksal Z, Turkan F, Alwasel S, 2016. The Effect of Caffeic Acid Phenethyl Ester (Cape) on Metabolic Enzymes Including Acetylcholinesterase, Butyrylcholinesterase, Glutathione S-Transferase, Lactoperoxidase, and Carbonic Anhydrase Isoenzymes I, Ii, Ix, and Xii. Journal of Enzyme Inhibition and Medicinal Chemistry 31(6): 1095-1101.
17. Imran S, Taha M, Ismail NH, Fayyaz S, Khan KM, Choudhary MI, 2016. Synthesis of Novel Bisindolylmethanes: New Carbonic Anhydrase Ii Inhibitors, Docking, and 3d Pharmacophore Studies. Bioorganic Chemistry 68: 90-104.
18. Kursun Aktar BS, Oruc-Emre EE, Demirtas I, Sahin Yaglioglu A, Karakucuk Iyidogan A, Guler C, Adem S, 2018. Synthesis and Biological Evaluation of Novel Chalcones Bearing Morpholine Moiety as Antiproliferative Agents. Turkish Journal of Chemistry 42(2): 482-+.
19. Lineweaver H, Burk D, 1934. Th E Determination of Enzyme Dissocation Constants. Journal of the American Chemical Society 56: 658-666.
20. Lolak N, Akocak S, Bua S, Sanku RKK, Supuran CT, 2019. Discovery of New Ureido Benzenesulfonamides Incorporating 1,3,5-Triazine Moieties as Carbonic Anhydrase I, Ii, Ix and Xii Inhibitors. Bioorganic & Medicinal Chemistry 27(8): 1588-1594.
21. Maren TH, Rayburn CS, Liddell NE, 1976. Inhibition by Anions of Human Red-Cell Carbonic Anhydrase-B - Physiological and Biochemical Implications. Science 191(4226): 469-472.
22. Mert S, Alim Z, Isgor MM, Beydemir S, Kasimogullari R, 2016. The Synthesis of Novel Pyrazole-3,4-Dicarboxamides Bearing 5-Amino-1,3,4-Thiadiazole-2-Sulfonamide Moiety with Effective Inhibitory Activity against the Isoforms of Human Cytosolic Carbonic Anhydrase I and Ii. Bioorganic Chemistry 68: 64-71.
23. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ, 2009. Autodock4 and Autodocktools4: Automated Docking with Selective Receptor Flexibility. Journal of Computational Chemistry 30(16): 2785-2791.
24. Oguz M, Kalay E, Akocak S, Nocentini A, Lolak N, Boga M, Yilmaz M, Supuran CT, 2020. Synthesis of Calix[4]Azacrown Substituted Sulphonamides with Antioxidant, Acetylcholinesterase, Butyrylcholinesterase, Tyrosinase and Carbonic Anhydrase Inhibitory Action. J Enzyme Inhib Med Chem 35(1): 1215-1223.
25. Ozil M, Balaydin HT, Senturk M, 2019. Synthesis of 5-Methyl-2,4-Dihydro-3h-1,2,4-Triazole-3-One's Aryl Schiff Base Derivatives and Investigation of Carbonic Anhydrase and Cholinesterase (Ache, Buche) Inhibitory Properties. Bioorganic Chemistry 86: 705-713.
26. Salmas RE, Mestanoglu M, Durdagi S, Senturk M, Kaya AA, Kaya EC, 2016. Kinetic and in Silico Studies of Hydroxy-Based Inhibitors of Carbonic Anhydrase Isoforms I and Ii. Journal of Enzyme Inhibition and Medicinal Chemistry 31(1): 31-37.
27. Singh P, Swain B, Thacker PS, Sigalapalli DK, Purnachander Yadav P, Angeli A, Supuran CT, Arifuddin M, 2020. Synthesis and Carbonic Anhydrase Inhibition Studies of Sulfonamide Based Indole-1,2,3-Triazole Chalcone Hybrids. Bioorganic Chemistry 99: 103839.
28. Sly WS, Hu PY, 1995. Human Carbonic-Anhydrases and Carbonic-Anhydrase Deficiencies. Annual Review of Biochemistry 64: 375-401.
29. Sly WS, Whyte M, Hewettemmett D, Yu YSL, Tashian RE, 1983. Carbonic Anhydrase-Ii Deficiency Identified as the Primary Defect in the Autosomal Recessive Syndrome of Osteopetrosis with Renal Tubular-Acidosis and Cerebral Calcification. Clinical Research 31(2): A456-A456.
30. Supuran CT, 2008. Carbonic Anhydrases: Novel Therapeutic Applications for Inhibitors and Activators. Nature Reviews Drug Discovery 7(2): 168-181.
31. Supuran CT, 2016. How Many Carbonic Anhydrase Inhibition Mechanisms Exist? Journal of Enzyme Inhibition and Medicinal Chemistry 31(3): 345-360.
32. Supuran CT, 2017. Advances in Structure-Based Drug Discovery of Carbonic Anhydrase Inhibitors. Expert Opinion on Drug Discovery 12(1): 61-88.
33. Supuran CT, Scozzafava A, Casini A, 2003. Carbonic Anhydrase Inhibitors. Medicinal Research Reviews 23(2): 146-189.
34. Supuran CT, Scozzafava A, Conway J, 2005. Carbonic Anhydrase: Its Inhibitors and Activators, MA: Taylor and Francis.
35. Turkan F, Cetin A, Taslimi P, Karaman M, Gulcin I, 2019. Synthesis, Biological Evaluation and Molecular Docking of Novel Pyrazole Derivatives as Potent Carbonic Anhydrase and Acetylcholinesterase Inhibitors. Bioorganic Chemistry 86: 420-427.
36. Turkoglu EA, Senturk M, Supuran CT, Ekinci D, 2017. Carbonic Anhydrase Inhibitory Properties of Some Uracil Derivatives. Journal of Enzyme Inhibition and Medicinal Chemistry 32(1): 74-77.
37. Tutar U, Kocyigit UM, Gezegen H, 2019. Evaluation of Antimicrobial, Antibiofilm and Carbonic Anhydrase Inhibition Profiles of 1,3-Bis-Chalcone Derivatives. Journal of Biochemical and Molecular Toxicology 33(4).
38. Verpoorte JA, Mehta S, Edsall JT, 1967. Esterase Activities of Human Carbonic Anhydrases B and C. The Journal of Biological Chemistry 242: 4221–4229.
39. Zheng YB, Wang L, Zhang W, Xu HW, Chang XT, 2012. Transgenic Mice over-Expressing Carbonic Anhydrase I Showed Aggravated Joint Inflammation and Tissue Destruction. Bmc Musculoskeletal Disorders 13.
40. Zheng YB, Xu B, Zhao Y, Gu H, Li C, Wang Y, Chang XT, 2015. Ca1 Contributes to Microcalcification and Tumourigenesis in Breast Cancer. Bmc Cancer 15.