Abstract
Tuberculosis, one of the oldest known human diseases, is still one of the major causes of mortality. Mycobacterium, a genus of Actinobacteria, is responsible for tuberculosis (Mycobacterium tuberculosis) and leprosy (Mycobacterium leprae). Because of producing high toxicity and resistance of existing drugs, the antitubercular drugs with less toxicity, potential activity and safer therapeutic profiles is an urgent need. Pyrazolo[3,4-d]pyrimidine compounds show various pharmacological activities including antitubercular. Molecular docking studies of eight pyrazolo[3,4-d]pyrimidine derivatives have been carried out with the mycobacterial β-oxidation trifunctional enzyme (mtTFE) using Autodock and Glide docking protocols. The docking results demonstrate good binding capabilities of these molecules with mtTFE. Molecular dynamics simulations of the best docked complexes of the compounds demonstrating better binding affinities and satisfactory ADME properties have been carried out using DESMOND for 10.0 ns duration. The average RMSD variation and simulation interaction study indicate that the complexes remain stable during the course of dynamics. However, molecules 6 and 7 exhibit better stability than other molecules and are the suitable candidates to be carried forward as a potential lead in the discovery of drugs to contest tuberculosis.
Similar content being viewed by others
References
Albery WJ, Foulds AW, Hall KJ, Hillman AR, Edgell RG, Orchard AF (1979) Thionine coated electrode for photogalvanic cells. Nature 282:793–797
Bekhit AA, Abdel-Azeim T (2004) Design, synthesis and biological evaluation of some pyrazole derivatives as anti-inflammatory-antimicrobial agents. Bioorg Med Chem 12:1935–1945
Bissantz C, Folkers G, Rognan D (2000) Protein based virtual screening of chemical database. 1. Evaluation of different docking/scoring combinations. J Med Chem 43:4759–4767
Bowers KJ, Chow E, Xu H, Dror RO, Eastwood MP, Gregersen BA, Klepeis JL, Kolossvary I, Moraes MA, Sacerdoti FD, Salmon JK, Shan Y, Shaw DE (2006) Scalable algorithms for molecular dynamics simulations on commodity clusters. In: Proceedings of the ACM/IEEE conference on supercomputers (SC06), Tampa, Florida, November 11–17
Carlomagno F, Vitagliano D, Guida T, Basolo F, Castellone MD, Melillo RM, Fusco A, Santro M (2003) Efficient inhibition of RET/papillary thyroid carcinoma oncogenic kinases by 4-amino-5-(4-chloro-phenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2). J Clin Endocrinol Metab 88:1897–1902
Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, Gordon SV, Eiglmeier K, Gas S (1998) Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393:537–544
Davies LP, Chow SC, Skeritt JH, Brown DJ, Johnston G (1984) Pyrazolo[3,4-d]pyrimidines as adenosine antagonists. Life Sci 34:2117–2128
DESMOND Molecular Dynamics System, version 3.1, D. E. Shaw Research, New York, NY (2012)
Elion GB, Callahan SW, Nathan H, Bieber S, Rundles RW, Hilching GH (1963) Potentiation by inhibition of drug degradation: 6-substituted purines and xanthine oxidase. Biochem Pharmacol 12:85–93
Friesner RA, Banks JL, Murphy RB, Halgreen TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelly M, Perry JK, Shaw DE, Francis P, Shenkin PS (2004) Glide a new approach for rapid accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 47:1739–1749
Friesner RA, Murphy RB, Reposky MP, Frye LL, Greenword JR, Halgreen TA, Sanchagrin PC, Mainz DT (2006) Extra precision Glide: docking and scoring incorporating a model of hydrophobic enclosure for protein ligand complexes. J Med Chem 49:6177–6196
Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Montgomery JA, Vreven JT, Kudin KN, Burant, JC, Millam JM, Iyengar SS, Tomasi J, Barone V, Mennucci B, Cossi M, Scalmani G, Rega N, Petersson GA, Nakatsuji H, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Klene M, Li X, Knox JE, Hratchian HP, Cross JB, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Ayala PY, Morokuma K, Voth GA, Salvador P, Dannenberg JJ, Zakrzewski VG, Dapprich S, Daniels AD, Strain MC, Farkas O, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Ortiz JV, Cui Q, Baboul AG, Clifford S, Cioslowski J, Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng CY, Nanayakkara A, Challacombe M, Gill PMW, Johnson B, Chen W, Wong MW, Gonzalez C, Pople JA (2003) GAUSSIAN 03, revision B.04. Gaussian, Inc., Pittsburgh
Guo S, Xue R, Li Y, Wanga SM, Ren L, Xu JJ (2012) The CFP10/ESAT6 complex of Mycobacterium tuberculosis may function as regulator of macrophage cell death at different stages of tuberculosis infection. Med Hypotheses 78:389–392
Jorgensen WL, Maxwell DS, Tirado-Rives J (1996) Development and testing of the OPLS all atom force field on conformational energetic and properties of organic liquids. J Am Chem Soc 118:11225–11236
Lawn SD, Zumla Al (2011) Tuberculosis. Lancet 378(9785):57–72
Lipinski CA (2000) Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods 44:235–249
Lipinski CA, Lombardo F, Doming BW, Feeney PJ (1997) Experimental and computational approach to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 23:3–25
Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) Automated docking using Lamarckinn genetic algorithm and empirical binding force energy function. J Comput Chem 19:1639–1662
Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) Autodock4 and Autodock Tools4: automated docking with selective receptor flexibility. J Comput Chem 30:2785–2791
Ngo SC, Zimhony O, Chung WJ, Sayahi H, Jacobs WR, Welch JohnT (2007) Inhibition of isolated Mycobacterium tuberculosis fatty acid synthase I by pyrazinamide analogs. Antimicrob Agents Chemother 51(7):2430–2435
Okafor OC (1977) Studies in the heterocyclic series XII, the chemistry and applications of aza and thia analogs of phenoxazine and related compounds. Hetrocycles 7:391–427
Olivier I, Loots DT (2011) An overview of tuberculosis treatments and diagnostics. What role could metabolomics play? J Cell Tissue Res 11:2655–2671
Prime, version 3.1, Schrödinger, LLC, New York, NY (2010)
Qikprop: version 3.5, Schrödinger, LLC, New York, NY (2010)
Schenone S, Brullo C, Musumeci F, Botta M (2010) Novel dual Src/Abl inhibitors for hematologic and solid malignancies. Expert Opin Invest Drugs 19:931–945
Schrödinger, LLC, New York (2010)
Scior T, Morales M, Garces I, Eisele SJ, Domeyer D, Lanfer S (2002) Antitubercular isoniazid and drug resistance of Mycobacterium tuberculosis: a review. Arch Pharm 335:511–525
Sherman W, Day T, Jacobson MP, Frisner RA (2006) Novel procedure for modeling ligand/receptor induced fit effects. J Med Chem 49:534–553
Shrivastava T, Ramachandran R (2007) Mechanistic insights from the crystal structures of a feast/famine regulatory protein from Mycobacterium tuberculosis H37Rv. Nucleic Acids Res 35:7324–7335
Srivastava HK, Chourasia M, Kumar D, Sastry GN (2011) Comparison of computational methods to model DNA minor groove binders. J Chem Inf Model 51:558–571
Tripathi RP, Tiwari N, Dwivedi N, Tiwari VK (2005) Fighting tuberculosis: an old disease with new challenges. Med Res Rev 25:93–131
Trivedi AR, Dholariya BH, Vakhariya CP, Dodiya DK, Ram HK, Katariya VB, Siddiqui AB, Shah VH (2012) Synthesis and antitubercular evaluation of some novel pyrazolo[3,4-d]pyrimidine derivatives. Med Chem Res 21:1887–1891
Venkatesan R, Wierenga RK (2013) Structure of mycobacterial β-oxidation trifunctional enzyme reveals its altered assembly and putative substrate channeling pathway. ACS Chem Biol 8:1063–1073
Verlet L (1967) Computer ‘‘experiments’’ on classical fluids I. Thermodynamical properties of Lennard-Jones molecules. Phys Rev 159:98–103
Yadava U, Singh M, Roychoudhury M (2013) Pyrazolo[3,4-d]pyrimidines as inhibitor of anti-coagulation and inflammation activities of phospholipase A2: insight from molecular docking studies. J Biol Phys 39:419–438
Yadava U, Gupta H, Yadav RK, Roychoudhury M (2014) Docking and molecular dynamics simulations of pyrazolo[3,4-d]pyrimidine-DNA complexes. Adv Sci Lett 20(7–9):1637–1643
Young DB (1998) Blueprint for the white plague. Nature 393:515–516
Acknowledgments
U. Yadava is thankful to DST, New Delhi and UGC New Delhi for the award of Fast Track Young Scientist (F.No. SR/FT/CS-78/2010) and Raman Fellowship for post doctoral studies in USA (F.No. 5-1/2013(IC)) respectively.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Yadava, U., Shukla, B.K. & Roychoudhury, M. Pyrazolo[3,4-d]pyrimidines as the inhibitors of mycobacterial β-oxidation trifunctional enzyme. Med Chem Res 24, 4002–4015 (2015). https://doi.org/10.1007/s00044-015-1441-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00044-015-1441-6