Abstract
Glaucoma is a neurodegenerative disease and second leading cause of blindness in western world. The disease is characterized by an elevated intraocular pressure. Carbonic anhydrase plays a major role by forming aqueous humor and its inhibition can reduce intraocular pressure by partially suppressing the secretion of aqueous humor. Thus in this study, we proposed to identify the potential novel compounds targeting the carbonic anhydrase. The diversity set-II molecules library consisting of 1880 compounds from National Cancer Institute were virtually screened (molecular docking) against human carbonic anhydrase protein. For the obtained best compounds, the nature of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO), which determine nucleophilic and electrophilic activity, were calculated by using density functional theory (DFT). The in silico screening suggested 5 best compounds that are effective in comparison to the dorzolamide, a widely used carbonic anhydrase inhibitor for glaucoma treatment. Of the five compounds, 4-nitro-7-[(1-oxidopyridin-1-ium-2-yl) thio] benzofurazan (ZINC01757986) exhibited the better binding affinity (− 9.2 cal/mol) in comparison to dorzolamide (− 7.2 kcal/mol). The DFT studies on novel identified compound, ZINC01757986 exhibited less HOMO–LUMO energy gap, low hardness and more softness (0.2305 eV, 0.1152 eV and 8.6805 eV) when compared to dorzalamide (0.9536 eV, 0.4768 eV and 2.0973 eV). These studies emphasize that ZINC01757986 can be used as potential carbonic anhydrase inhibitor and lead compounds for the development of an effective anti-glaucoma drug. The results emphasize that these compounds could be potential lead molecules for further structure-based discovery of antiglaucoma drugs.
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References
Alm A, Nilsson SF (2009) Uveoscleral outflow: a review. Exp Eye Res 88:e46632
Berman HM, Battistuz T, Bhat TN, Bluhm WF, Bourne PE, Burkhardt K, Feng Z, Gilliland GL, Iype L, Jain S, Fagan P (2002) The protein data bank. Acta Crystallogr D 58:899–907
BIOVIA Discovery studio 2017 R2 Client (2017) Dassault Systèmes, San Diego
CADD Group Chemoinformatics Tools and User Services at National Cancer Institute. https://cactus.nci.nih.gov/download/nci/. Accessed 23 April 2019.
Carta F, Akdemir A, Scozzafava A, Emanuela M, Supuran CT (2013) Xanthates and trithiocarbonates strongly inhibit carbonic anhydrases and show antiglaucoma effects in vivo. J Med Chem 56:4691–4700
Chen J, Runyan SA, Robinson MR (2011) Novel ocular antihypertensive compounds in clinical trials. Clin Ophthalmol 5:667–677
Cheng JW, Cheng SW, Ma XY, Cai JP, Li Y, Lu GC, Wei RL (2012) Myocilin polymorphisms and primary open-angle glaucoma: a systematic review and meta-analysis. PLoS ONE 7:46–632
Cholkar K, Trinh HM, Pal D, Mitra AK (2015) Discovery of novel inhibitors for the treatment of glaucoma Expert Opin Drug Discov 10: 293–313.
Coleman AL, Miglior S (2008) Risk factors for glaucoma onset and progression. Surv Ophthalmol 53:S3–S10
de Leval X, Ilies M, Casini A, Dogné JM, Scozzafava A, Masini E, Mincione F, Starnotti M, Supuran CT (2004) Carbonic anhydrase inhibitors: synthesis and topical intraocular pressure lowering effects of fluorine-containing inhibitors devoid of enhanced reactivity. J Med Chem 47:2796–2804
Dutt VA, Patel A, Cholkar K, Mitra AK (2012) Recent patents on emerging therapeutics for the treatment of glaucoma, age related macular degeneration and uveitis. Curr Biomed Eng 5:83–101
Fabrizi F, Mincione F, Somma T, Scozzafava G, Galassi F, Masini E, Impagnatiello F, Supuran CT (2012) A new approach to antiglaucoma drugs: carbonic anhydrase inhibitors with or without no donating moieties. Mechanism of action and preliminary pharmacology. J Enzyme Inhib Med Chem 27:138–147
Fautsch MP, Johnson DH (2006) Aqueous humor outflow: what do we know? Where will it lead us? Invest Ophthalmol Vis Sci 47:4181–4187
Foresman JB, Frisch A (1995) Exploring chemistry with electronic structure methods. Gaussian, Pittsburgh
Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA (2009) Gaussian. Gaussian Inc., Wallingford
Goel M, Picciani RG, Lee RK, Bhattacharya SK (2010) Aqueous humor dynamics: a review. Open Opthalmol J 4:52–59
Gong LL, Fang LH, Peng JH, Liu AL, Du GH (2010) Integration of virtual screening with high-throughput screening for the identification of novel Rho-kinase I inhibitors. J Biotechnol 145:295–303
Hollo G, Chiselita D, Petkova N, Cvenkel B, Liehneova I, Izgi B, Berta A, Szaflik J, Turacli E, Stewart WC (2006) The efficacy and safety of timolol maleate versus brinzolamide each given twice daily added to travoprost in patients with ocular hypertension or primary open-angle glaucoma. Eur J Ophthalmol 16:816–823
Li FR, Fan ZF, Qi SJ, Wang YS, Wang J, Liu Y, Cheng MS (2017) Design, synthesis, molecular docking analysis, and carbonic anhydrase IX inhibitory evaluations of novel N-substituted-β-d-glucosamine derivatives that incorporate benzenesulfonamides. Molecules 22:785
Lipinski CA (2004) Lead-and drug-like compounds: the rule-of-five revolution. Drug Discov Today Technol 1:337–341
Mark HH (2009) Aqueous humor dynamics in historical perspective. Surv Ophthalmol 55:89–100
Nesher R, Ticho U (2003) Switching from systemic to the topical carbonic anhydrase inhibitor dorzolamide: effect on the quality of life of glaucoma patients with drug-related side effects. Isr Med Assoc J 5:260–263
O’Connor DJ, Martone JF, Mead A (2002) Additive intraocular pressure lowering effect of various medications with latanoprost. Am J Ophthalmol 133:836–837
O'Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GH (2011) Open babel: an open chemical toolbox. J Cheminform 3:33
Pauling L (1960) The nature of the chemical bond. Cornell University Press, Ithaca
Quigley HA, Broman AT (2006) The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 90:262–267
Scozzafava A, Menabuoni L, Mincione F, Briganti F, Mincione G, Supuran CT (2000) Carbonic anhydrase inhibitors: perfluoroalkyl/aryl-substituted derivatives of aromatic/heterocyclic sulfonamides as topical intraocular pressure-lowering agents with prolonged duration of action. J Med Chem 43:4542–4551
Senet P (1997) Chemical hardnesses of atoms and molecules from frontier orbitals. Chem Phys Lett 275:527–532
Shahidullah M, To CH, Pelis RM, Delamere NA (2009) Studies on bicarbonate transporters and carbonic anhydrase in porcine nonpigmented ciliary epithelium. Invest Ophthalmol Vis Sci 50:1791–1800
Shanmugam G, Lee SK, Jeon J (2018) Identification of potential nematicidal compounds against the pine wood nematode, Bursaphelenchus xylophilus through an in silico approach. Molecules 23:1828
Sharma OP, Pan A, Hoti SL, Jadhav A, Kannan M, Mathur PP (2012) Modeling, docking, simulation, and inhibitory activity of the benzimidazole analogue against -tubulin protein from Brugia malayi for treating lymphatic filariasis. Med Chem Res 21:2415–2427
Silver LH (2000) Ocular comfort of brinzolamide 1.0% ophthalmic suspension compared with dorzolamide 2.0% ophthalmic solution: results from two multicenter comfort studies. Brinzolamide comfort study group. Surv Ophthalmol 44:S141–S145
Steele RM, Benedini F, Biondi S, Borghi V, Carzaniga L, Impagnatiello F, Miglietta D, Chong WK, Rajapakse R, Cecchi A, Temperini C, Supuran CT (2009) Nitric oxide-donating carbonic anhydrase inhibitors for the treatment of open-angle glaucoma. Bioorg Med Chem Lett 19:6565–6570
Tang M, Fu Y, Fan Y, Fu MS, Zheng Z, Xu X (2017) In-silico design of novel myocilin inhibitors for glaucoma therapy. Trop J Pharm Res 16:2527–2533
Tatham et al (2014) Tatham AJ, Weinreb RN, Medeiros FA (2014) Strategies for improving early detection of glaucoma: the combined structure-function index. Clin Ophthalmol 8:611–621
Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31:455–461
Wang SK, Chang RT (2014) An emerging treatment option for glaucoma: Rho kinase inhibitors. Clin Ophthalmol 8:883–890
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Figure S1: The docking complex and interactions of ZINC01045090 (binding affinity: − 7.2 kcal/mol) with human carbonic anhydrase IX. Figure S2: The docking complex and interactions of ZINC05479118 (binding affinity: − 7.5 kcal/mol) with human carbonic anhydrase IX. Figure S3: The docking complex and interactions of ZINC05180959 (binding affinity: − 7.3 kcal/mol) with human carbonic anhydrase IX. Figure S4: The docking complex and interactions of ZINC17465958 (binding affinity: − 8.0 kcal/mol) with human carbonic anhydrase IX. Supplementary file1 (DOCX 306 kb)
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Anitha, D., Suganthi, M., Gnanendra, S. et al. Identification of Potential Carbonic Anhydrase Inhibitors for Glaucoma Treatment Through an In-Silico Approach. Int J Pept Res Ther 26, 2147–2154 (2020). https://doi.org/10.1007/s10989-019-10011-8
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DOI: https://doi.org/10.1007/s10989-019-10011-8