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Computational evaluation of 2-amino-5-sulphonamido-1,3,4-thiadiazoles as human carbonic anhydrase-IX inhibitors: an insight into the structural requirement for the anticancer activity against HEK 293

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Abstract

Carbonic anhydrase inhibitors are very interesting target for designing anticancer agents. A computational procedure was performed on some thiadiazoles derived from carbonic anhydrase inhibitor acetazolamide. Two important procedures in computational drug discovery, namely docking for modeling ligand–receptor interactions and quantitative structure–activity relationships were employed. The relationship between cytotoxic activity and various descriptors was established by stepwise multiple regression analysis. The analyses have produced well predictive and statistically significant quantitative structure–activity relationships models, which were further cross validated. Among several models, one model has good statistical significance (r = 0.89, F test = 6.88, S = 0.33, chance correlation < 0.01), indicates that steric descriptors like EleE are contributing positively to the biological activity, electronic descriptors like connolly molecular surface area and Chi descriptors like chi0 and information theory index like IdAvg are contributing negatively to the biological activity and play a significant role in receptor binding which helps to design some expectedly potent compounds. In order to confirm the obtained results through this ligand-based method, docking was performed on the selected compounds by the use of Schrödinger GLIDE program. Incorporating available biochemical and computational data to the model by correcting the conformation of a single residue lining the binding pocket resulted in significantly improved docking poses. The molecular modeling study allowed confirming the preferential binding mode of reported compounds inside the active site.

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References

  • Abrahum DJ (2003) Burger’s medicinal chemistry and drug discovery: principle and practice, vol 1, 6th edn. Wiley Interscience, New York, NY

    Book  Google Scholar 

  • Alterioa V, Hilvo M, Di Fiore A, Supuran CT, Pan P, Parkkila S, Scaloni A, Pastorek J, Pastorekova S, Pedone C, Scozzafava A, Montia SM, De Simone G (2009) Crystal structure of the catalytic domain of the tumor associated human carbonic anhydrase IX. Proc Natl Acad Sci USA 106:16233–16238

    Article  Google Scholar 

  • Ashida S, Nishimori I, Tanimura M, Onishi S, Shuin T (2002) Effects of von Hippel–Lindau gene mutation and methylation status on expression of transmembrane carbonic anhydrases in renal cell carcinoma. J Cancer Res Clin Oncol 128(10):561–568

    Article  CAS  PubMed  Google Scholar 

  • Brzozowski Z, Slawinski J, Saczewski F, Innocenti A, Supuran CT (2010) Carbonic anhydrase inhibitors: synthesis and inhibition of the human cytosolic isozymes I and II and transmembrane isozymes IX, XII (cancer-associated) and XIV with 4-substituted 3-pyridinesulfonamides. Eur J Med Chem 45:2396–2404

    Article  CAS  PubMed  Google Scholar 

  • Cecchi A, Hulikova A, Pastorek J, Pastorekova S, Scozzafava A, Winum JY, Montero JL, Supuran CT (2005) Carbonic anhydrase inhibitors. Design of fluorescent sulfonamides as probes of tumour-associated carbonic anhydrase IX that inhibit isozyme IX-mediated acidification of hypoxic tumours. J Med Chem 48(15):4834–4841

    Article  CAS  PubMed  Google Scholar 

  • Chegwidden WR, Spencer IM, Supuran CT (2001) The roles of carbonic anhydrase in cancer. In: Xue G, Xue Y, Xu Z, Hammond GL, Lim AH (ed) Gene families: studies of DNA, RNA, enzymes, and proteins. World Scientific, Singapore, p 157–169

    Chapter  Google Scholar 

  • Chhajed MR, Khedekar PB, Mundhey AS (2007) Synthesis and free radical scavenging activity of some 1,3,4-thiazole derivatives. Indian J Heterocycl Chem 16:259–262

    CAS  Google Scholar 

  • Chhajed MR, Shrivastava AK, Taile VS (2013) Design and syntheses of some new 5-[benzene sulphonamido]-1,3,4-thiadiazol-2-sulphonamide as potent antiepileptic agent. Macroheterocycles 6(2):199–209. doi:10.6060/mhc130116c

    Article  CAS  Google Scholar 

  • Chhajed MR, Shrivastava AK, Taile VS (2014) Synthesis of 5-arylidine amino-1,3,4-thiadiazol-2-[(N-substituted benzyol)]sulphonamides endowed with potent antioxidants and anticancer activity induces growth inhibition in HEK293, BT474 and NCI-H226 cells. Med Chem Res 23:3049–3064. doi:10.1007/s00044-013-0890-z

    Article  CAS  PubMed  Google Scholar 

  • Chandrabose S, Tripathi SK, Reddy KK, Singh SK (2011) Tool development for prediction of pIC50 values—a pIC50 values from the IC50 value calculator. Curr Trends Biotechnol Pharm 5(2):1104–1109

    Google Scholar 

  • Chen IJ, Foloppe NJ (2010) Drug-like bioactive structures and conformational coverage with the LigPrep/ConfGen suite: comparison to programs MOE and catalyst. J Chem Inf Model 50(5):822–839

    Article  CAS  PubMed  Google Scholar 

  • Cohen P (2002) Protein kinases—the major drug targets of the twenty-first century? Nat Rev Drug Discov 1:309–315

    Article  CAS  PubMed  Google Scholar 

  • Desai NC, Shukla HK, Astik RR, Thaker KA (1984) Studies on some thiosemicarbazones and 1,3,4-thiadiazolines as potential antitubercular and antibacterial agents. J Indian Chem Soc LXI:168–196

    Google Scholar 

  • Enkvist E, Lavogina D, Raidaru G, Vaasa A, Viil I, Lust M, Viht K, Uri A (2006) Conjugation of adenosine and hexa-(d-arginine) leads to a nanomolar bisubstrate-analog inhibitor of basophilic protein kinases. J Med Chem 49:7150–7159

    Article  CAS  PubMed  Google Scholar 

  • Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT (2004) Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 47(7):1739–1749

    Article  CAS  PubMed  Google Scholar 

  • Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA (2006) Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein–ligand complexes. J Med Chem 49:6177–6196

    Article  CAS  PubMed  Google Scholar 

  • Fujikawa-Adachi K, Nishimori I, Taguchi T, Onishi S (1999) Human carbonic anhydrase XIV (CA14): cDNA cloning, mRNA expression, and mapping to chromosome 1. Genomics 61(1):74–81

    Article  CAS  PubMed  Google Scholar 

  • Gill AL, Verdonk M, Boyle RG, Taylor R (2007) A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. Curr Top Med Chem 7(14):1408–1422

    Article  CAS  PubMed  Google Scholar 

  • Gupta A, Mishra P, Kashaw SK, Jatav V, Stables JP (2008) Synthesis of 3-aryl amino/amino-4-aryl-5-imino-D2-1,2,4-thiadiazoline and evaluated for anticonvulsant activity. Eur J Med Chem 43(4):749–754

    Article  CAS  PubMed  Google Scholar 

  • Gupta AK, Arockia BM, Kaskhedikar SG (2004) VALSTAT: validation program for quantitative structure activity relationship studies. Indian J Pharm Sci 66:396–402

    CAS  Google Scholar 

  • Hansch C, Leo A (1979) Substituent constants for correlation analysis in chemistry and biology. Wiley, New York, NY

    Google Scholar 

  • Hanna MA, Girges MM, Rasala D, Gawinecki R (1995) Synthesis and pharmacological evaluation of some novel 5-(pyrazol-3-yl)-thiadiazole and oxadiazole derivatives as potential hypoglycemic agents. Arzneim-Forsch Drug Res 45(10):1074–1078

    CAS  Google Scholar 

  • Hilvo M, Baranauskiene L, Salzano MA, Scaloni A, Matulis D, Innocenti A, Scozzafava A, Monti SM, Di Fiore A, De Simone G, Lindfors M, Jänis J, Valjakka J, Pastoreková S, Pastorek J, Kulomaa MS, Nordlund HR, Supuran CT, Parkkila S (2008) Biochemical characterization of CA IX, one of the most active carbonic anhydrase isozymes. J Biol Chem 283:27799–27809

    Article  CAS  PubMed  Google Scholar 

  • Jain A, Chaturvedi SC (2009) QSAR study on 6-substituted benzimidazoles: an insight into the structural requirement for the angiotensin II AT1 receptor antagonist. Sci Pharm 77:555–565

    Article  CAS  Google Scholar 

  • Jatav V, Mishra P, Kashaw S, Stables JP (2008) CNS depressant and anticonvulsant activities of some novel 3-[5-substituted-1,3,4-thiadiazole-2-yl]-2-styryl quinazoline-4(3H)-ones. Eur J Med Chem 43(9):1945–1954

    Article  CAS  PubMed  Google Scholar 

  • Kamb A (2005) Opinion: what’s wrong with our cancer models? Nat Rev Drug Discov 4(2):161–165

    Article  CAS  PubMed  Google Scholar 

  • Kaminski GA, Friesner RA, Tirado-Rives J, Jorgensen WL (2001) Evaluation and reparametrization of the OPLS-AA force field for protein via comparison with accurate quantum chemical calculations on peptides. J Phys Chem B 105:6474–6477

    Article  CAS  Google Scholar 

  • Kaunisto K, Parkkila S, Rajaniemi H, WaheedA, Grubb J, Sly WS (2002) Carbonic anhydrase XIV: luminal expression suggests key role in renal acidification. Kidney Int 61(6):2111–2118

    Article  CAS  PubMed  Google Scholar 

  • Kleandrova VV, Speck Planche A (2017) Multitasking model for computer-aided design and virtual screening of compounds with high anti-HIV activity and desirable ADMET properties. In: Speck-Planche A (ed) Multi-scale approaches in drug discovery: from empirical knowledge to in silico experiments and back, 1st edn. Elsevier, Oxford, p 55–81

    Chapter  Google Scholar 

  • Krissinel E, Henrick K (2007) Inference of macromolecular assemblies from crystalline state. J Mol Biol 372:774–797

    Article  CAS  PubMed  Google Scholar 

  • Kumar A, Shrivastava VK, Archana (2003) Synthesis of newer indolyl thiadiazoles and their thiazolidinones and formazans as potential anticonvulsant agents. Indian J Pharm Sci 65(4):358–362

    Google Scholar 

  • Kumar D, Maruthi Kumar N, Chang KH, Shah K (2010) Synthesis and anticancer activity of 5-(3-indolyl)-1,3,4-thiadiazoles. Eur J Med Chem 45(10):4664–4668

    Article  CAS  PubMed  Google Scholar 

  • Laskowski RA, Hutchinson EG, Michie AD, Wallace AC, Jones ML, Thornton JM (1997) PDBsum: a web-based database of summaries and analyses of all PDB structures. Trends Biochem Sci 22:488–490

    Article  CAS  PubMed  Google Scholar 

  • Lin X, Murray JM, Rico AC, Wang MX, Chu DT, Zhou Y, Del Rosario M, Kaufman S, Ma S, Fang E, Crawford K, Jefferson AB (2006) Discovery of 2-pyrimidyl-5-amidothiophenes as potent inhibitors for AKT: synthesis and SAR studies. Bioorg Med Chem Lett 16:4163–4168

    Article  CAS  PubMed  Google Scholar 

  • Luan F, Cordeiro MNDS, Alonso N, Garcia-Mera X, Caamano O, Romero-Duran FJ, Yanez M, Gonzalez-Diaz H (2013) TOPS-MODE model of multiplexing neuroprotective effects of drugs and experimental-theoretic study of new 1,3-rasagiline derivatives potentially useful in neurodegenerative diseases. Bioorg Med Chem 21(7):1870–1879

    Article  CAS  PubMed  Google Scholar 

  • Manoharan P, Vijayan RSK, Ghoshal N (2010) Rationalizing fragment based drug discovery for BACE1: insights from FB-QSAR, FB-QSSR, multi objective (MO-QSPR) and MIF studies. J Comput Aided Mol Des 24(10):843–864

    Article  CAS  PubMed  Google Scholar 

  • Minchinton AI, Tannock IF (2006) Drug penetration in solid tumours. Nat Rev Cancer 6(8):583–592

    Article  CAS  PubMed  Google Scholar 

  • Nam NH, Lee S, Ye G, Sun G, Parang K (2004) ATP-phosphopeptide conjugates as inhibitors of Src tyrosine kinases. Bioorg Med Chem 12:5753–5766

    Article  CAS  PubMed  Google Scholar 

  • Noble ME, Endicott JA, Johnson LN (2004) Protein kinase inhibitors: insights into drug design from structure. Science 303:1800–1805. doi:10.1126/science.1095920

    Article  CAS  PubMed  Google Scholar 

  • Noolvi MN, Patel HM, Singh N, Gadad AK, Cameotra SS, Badiger A (2011) Synthesis and anticancer evaluation of novel 2-cyclopropylimidazo[2,1-b][1,3,4]-thiadiazole derivatives. Eur J Med Chem 46(9):4411–4418

    Article  CAS  PubMed  Google Scholar 

  • Oruc EE, Rollas S, Kandemirli F, Shvets N, Dimoglo AS (2004) 1,3,4-Thiadiazole derivatives. Synthesis, structure elucidation, and structure-antituberculosis activity relationship investigation. J Med Chem 47:6760–6767

    Article  CAS  PubMed  Google Scholar 

  • Pastorekova S, Parkkila S, Parkkila AK, Opavsky R, Zelnik V, Saarnio J, Pastorek J (1997) Carbonic anhydrase IX, MN/CA IX: analysis of stomach complementary DNA sequence and expression in human and rat alimentary tracts. Gastroenterology 112(2):398–408

    Article  CAS  PubMed  Google Scholar 

  • Pelech S (2004) Tracking cell signaling protein expression and phosphorylation by innovative proteomic solutions. Curr Pharm Biotechnol 5:69–77

    Article  CAS  PubMed  Google Scholar 

  • Pandey VK, Tusi S, Tusi Z, Raghubir R, Dixit M, Joshi MN, Bajpai SK (2004) Thiadiazolyl quinazolones as potential antiviral and antihypertensive agents. Indian J Chem 43B:180–183

    CAS  Google Scholar 

  • Parkkila S, Kivele AJ, Kaunisto K, Parkkila AK, Hakkola J, Rajaniemi H, Waheed A, Sly WS (2002) The plasma membrane carbonic anhydrase in murine hepatocytes identified as isozyme XIV. BMC Gastroenterol 2:13. doi:10.1186/1471-230X-2-13

    Article  PubMed  PubMed Central  Google Scholar 

  • Parkkila S, Parkkila AK, Rajaniemi H, Shah GN, Grubb JH, Waheed A, Sly WS (2001) Expression of membrane-associated carbonic anhydrase XIV on neurons and axons in mouse and human brain. Proc Natl Acad Sci USA 98(4):1918–1923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parkkila S, Rajaniemi H, Parkkila AK, Kivelä J, Waheed A, Pastorekova S, Pastorek J, Sly WS (2000) Carbonic anhydrase inhibitor suppresses invasion of renal cancer cells in vitro. Proc Natl Acad Sci USA 97:2220–2224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pastorek J, Pastorekova S, Callebaut I, Marnon JP, Zelnik V, Opavsky R, Zatovicova M, Liao S, Portetelle D, Stanbridge EJ, Zavada J, Burny A, Kettmann R (1994) Cloning and characterization of MN, a human tumor-associated protein with a domain homologous to carbonic anhydrase and a putative helix-loop-helix DNA binding segment. Oncogene 9(10):2877–2888

    CAS  PubMed  Google Scholar 

  • Patil R, Biradar JS (2001) Synthesis and pharmacological evaluation of Substituted–2-triazolo(3,4-b)[1,3,4,]-thiadiazoles. Indian J Pharm Sci 63(4):299–305

    Google Scholar 

  • Pattan SR, Kekare P, Dighe NS, Nirmal SA, Musmade DS, Parjane SK, Daithankar AV (2009) Synthesis and biological evaluation of some 1,3,4-thiadiazoles. J Chem Pharm Res 1(1):191–198

    CAS  Google Scholar 

  • Salimon J, Salih N, Yousif E, Hameed A, Ibraheem H (2010) Synthesis and antibacterial activity of some new 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives. Aust J Basic Appl Sci 4(7):2016–2021

    CAS  Google Scholar 

  • Sharma R, Sainy J, Chatuvedi SC (2008) 2-Amino-5-sulfanyl-1,3,4-thiadiazoles: a new series of selective cyclooxygenase-2 inhibitors. Acta Pharm 58(3):317–326

    CAS  PubMed  Google Scholar 

  • Sharma R, Talesara GL, Nagda DP (2006) Synthesis of various isoniazidothiazolidinones and their imidoxy derivatives of potential biological interest. Arkivoc 1:1–12

    Google Scholar 

  • Shelley JC, Cholleti A, Frye LL, Greenwood JR, Timlin MR, Uchimaya M (2007) Epik: a software program for pK (a) prediction and protonation state generation for drug-like molecules. J Comput Aided Mol Des 2007(12):681–691

    Article  Google Scholar 

  • Shen K, Cole PA (2003) Conversion of a tyrosin kinase protein substrate to a high affinity ligand by ATP linkage. J Am Chem Soc 125:16172–16173

    Article  CAS  PubMed  Google Scholar 

  • Shrivastava SK, Shrivastava S, Shrivastava SD (1999) Synthesis of new carbazolyl-thiadiazole-2-oxoazetidines: antimicrobial, anticonvulsant and anti-inflammatory agents. Indian J Chem 38B:183–187

    Google Scholar 

  • Speck-Planche A, Kleandrova VV, Luan F, Cordeiro MNDS (2013) Unified multi-target approach for the rational in silico design of anti-bladder cancer agents. Anticancer Agents Med Chem 13(5):791–800

    Article  CAS  PubMed  Google Scholar 

  • Speck-Planche A, Cordeiro MNDS (2014) Chemoinformatics for medicinal chemistry: in silico model to enable the discovery of potent and safer anti-cocci agents. Future Med Chem 6(18):2013–2028

    Article  CAS  PubMed  Google Scholar 

  • Speck Planche A, Cordeiro MNDS (2017) Speeding up the virtual design and screening of therapeutic peptides: simultaneous prediction of anticancer activity and cytotoxicity. In: Speck-Planche A (ed) Multi-scale approaches in drug discovery: from empirical knowledge to in silico experiments and back, 1st edn. Elsevier, Oxford, p 127–147

    Chapter  Google Scholar 

  • Stillings MR, Welbourn AP, Walter DS (1986) Substituted 1,3,4-thiadiazoles with anticonvulsant activity. 2. Aminoalkyl derivatives. J Med Chem 29:2280–2284

    Article  CAS  PubMed  Google Scholar 

  • Supuran CT (2008) Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov 7(2):168–181

    Article  CAS  PubMed  Google Scholar 

  • Supuran CT, Scozzafava A (2000) Carbonic anhydrase inhibitors and their therapeutic potential. Expert Opin Ther Pat 10:575–600

    Article  CAS  Google Scholar 

  • Supuran CT, Scozzafava A, Casini A (2003) Carbonic anhydrase inhibitors and their therapeutic potential. Med Res Rev 23(2):146–189

    Article  CAS  PubMed  Google Scholar 

  • Supuran CT, Scozzafava A, Conway I (2004) Carbonic anhydrase, its inhibitors and activators. CRC, New York, NY

    Google Scholar 

  • Svastova E, Hulikova A, Rafajova M, Zatovicova M, Gibadulinova A, Casini A, Cecchi A, Scozzafava A, Supuran CT, Pastorek J, Pastorekova S (2004) Hypoxia activates the capacity of tumour associated carbonic anhydrase IX to acidify extracellular pH. FEBS Lett 577(3):439–445

    Article  CAS  PubMed  Google Scholar 

  • Tan YT, Tillett DJ, Mckay IA (2000) Molecular strategies for overcoming antibiotic resistance in bacteria. Mol Med Today 6(8):309–314

    Article  CAS  PubMed  Google Scholar 

  • Tureci O, Sahin U, Vollmar E, Siemer S, Gottert E, Seitz G, Parkkila AK, Shah GN, Grubb JH, Pfreundschuh M, Sly WS (1998) Human carbonic anhydrase XII: cDNA cloning, expression, and chromosomal localization of a carbonic anhydrase gene that is over expressed in some renal cell cancers. Proc Natl Acad Sci USA 95(13):7608–7613. doi:10.1073/pnas.95.13.7608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Varandas LS, Fraga CAM, Miranda ALP, Barreiro EJ (2005) Design, synthesis and pharmacological evaluation of new nonsteroidal anti-inflammatory 1,3,4-thiadiazole derivatives. Lett Drug Des Discov 2(1):62–67

    Article  CAS  Google Scholar 

  • Vincent TA (2000) Current and future antifungal therapy: new targets for antifungal therapy. Int J Antimicrob Agents 16:317–321

    Article  Google Scholar 

  • Vyas VK, Jain A, Mahajan SC (2009) Insight into the structural requirement of 2-alkyl-4-(biphenylmethoxy) quinolones as nonpeptide angiotensin II receptor antagonist. Sci Pharma 77:33–45

    Article  CAS  Google Scholar 

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Acknowledgements

The authors are thankful to the Principal, RC Patel College of Pharmacy, Shirpur and the HOD, School of Pharmacy, DAVV, Indore for providing facilities to complete this work.

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, Indore Institute of Pharmacy, Rau-Pithampur Road, Opp. IIM, Indore, Rau, Indore, MP, India

    Mahavir Chhajed, Sumeet Prachand & Sanjay Jain

  2. Department of Pharmaceutical Chemistry, Suresh Gyan Vihar University, Mahal Jagat Pura, Jaipur, India

    Mahavir Chhajed & Sumeet Prachand

  3. Department of Pharmaceutical Chemistry, NNM College of Pharmacy, Nawabganj, Gonda, UP, India

    Anil K. Shrivastava

  4. Department of Pharmaceutical Chemistry, Dr. A.P.J. Abdul Kalam University, Indore, MP, India

    Atika Chhajed

  5. Department of Chemistry, R.T.M. Nagpur University, Nagpur, MS, India

    Vijay Taile

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  1. Mahavir Chhajed
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Correspondence to Mahavir Chhajed.

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Chhajed, M., Shrivastava, A.K., Chhajed, A. et al. Computational evaluation of 2-amino-5-sulphonamido-1,3,4-thiadiazoles as human carbonic anhydrase-IX inhibitors: an insight into the structural requirement for the anticancer activity against HEK 293. Med Chem Res 26, 2272–2292 (2017). https://doi.org/10.1007/s00044-017-1929-3

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