Deepthi D. Kodical, Jainey P. James, Deepthi K, Pankaj Kumar, Chinchumol Cyriac, Gopika K.V.
Deepthi D. Kodical, Jainey P. James*, Deepthi K, Pankaj Kumar, Chinchumol Cyriac, Gopika K.V.
NGSMIPS CADD Lab, Department of Pharmaceutical Chemistry, NGSM Institute of Pharmaceutical Sciences, Nitte (Deemed to be University), Paneer, Deralakatte, Mangalore-575 018, Karnataka, India.
Volume - 13,
Issue - 9,
Year - 2020
Cyclooxygenase (COX), is an enzyme that is responsible for the formation of prostanoids, including thromboxane and prostaglandins. Prostaglandins promote inflammation. Blockage of COX enzymes reduces prostaglandins and thus their effects are reduced. The present study focuses on In silico ADMET, molecular docking studies and binding energy calculations of ten pyrimidine derivatives as cox-1 and cox-2 inhibitors. Molecular docking studies were conducted on two target enzymes. Energy minimisation of the ligands was carried out using ligprep. They were docked to the active site of the proteins using the extra precision mode of glide module. The docked poses were ranked according to their docking score and binding energy with the enzymes. Compound PY4 showed better docking score with cox-1 (-6.081 kcal/mol) and compound PY5 showed good docking score with cox-2 (-8.602 kcal/mol). All compounds were found to have good docking and binding affinity scores when compared to the standards. Thus it reveals that the synthesised compounds act as anti-inflammatory agents by inhibiting cox-1 and cox-2 enzymes.
Cite this article:
Deepthi D. Kodical, Jainey P. James, Deepthi K, Pankaj Kumar, Chinchumol Cyriac, Gopika K.V. ADMET, Molecular docking studies and binding energy calculations of Pyrimidine-2-Thiol Derivatives as Cox Inhibitors. Research J. Pharm. and Tech 2020; 13(9):4200-4206. doi: 10.5958/0974-360X.2020.00742.8
Deepthi D. Kodical, Jainey P. James, Deepthi K, Pankaj Kumar, Chinchumol Cyriac, Gopika K.V. ADMET, Molecular docking studies and binding energy calculations of Pyrimidine-2-Thiol Derivatives as Cox Inhibitors. Research J. Pharm. and Tech 2020; 13(9):4200-4206. doi: 10.5958/0974-360X.2020.00742.8 Available on: https://rjptonline.org/AbstractView.aspx?PID=2020-13-9-30
1. Chaudhary SK: Quitessence of Medical Pharmacology. Experimental Therapeutics 400.Volume 166. Kolkata: New Central Book Agency (P) Ltd; 2001:96.
2. Denko CW: A role of neuropeptides in inflammation. In Biochemistry of Inflammation. Edited by: Whicher JT, Evans SW. London: Kluwer Pub; 1992:177-181.
3. Watson DJ, Harper SE, Zhao PL, Quan H, Bolognese JA, Simon TJ (). Gastrointestinal tolerability of the selective cyclooxygenase-2 (cox-2) inhibitorrofecoxib compared with nonselective cox-1 and cox-2 inhibitors onsteoarthritis. Arch intern Med. 2000;160:2998-03.
4. Chhajed SS, Hiwanj PB, Bastikar VA, Upasani CD, Udavant PB, Dhake AS, Mahajan NP () Structure Based Design and In-Silico Molecular Docking Analysis of Some Novel Benzimidazoles. Int J Chem Tech Res.2010;2:1135-40.
5. Zarghi A, Arfaei S. Selective COX-2 inhibitors: a review of their structure-activity relationships. Iranian journal of pharmaceutical research: IJPR. 2011;10(4):655.
6. Magda AA, Abdel-Aziz NI, Alaa AM, El-Azab AS, Asiri YA, ElTahir KE. Design, synthesis, and biological evaluation of substituted hydrazone and pyrazole derivatives as selective COX-2 inhibitors: Molecular docking study. Bioorganic and medicinal chemistry. 2011;19(11):3416-24.
7. Dandiya PC, Kulkarni SK: Introduction to Pharmacology-Including Toxicology and Practicals. 5th edition. Delhi: Vallabh Prakashan; 1995:131-132.
8. Pavlo V. Zadorozhnii, Vadym V. Kiselev, Nataliia O. Teslenko, Aleksandr V. Kharchenko, Ihor O. Pokotylo, Oxana V. Okhtina, Oxana V. Kryshchyk. In Silico Prediction and Molecular Docking Studies of N-Amidoalkylated Derivatives of 1,3,4-Oxadiazole as COX-1 and COX-2 Potential Inhibitors. Research J. Pharm. and Tech. 2017;10(11):3957-63.
9. Parameswari. P, Devika. R. In silico Molecular Docking Studies of Quercetin Compound against Anti-inflammatory and Anticancer Proteins. Research J. Pharm. and Tech. 2019; 12(11):5505-09.
10. Chaudhary KK, Mishra N. A Review on Molecular Docking: Novel Tool for Drug Discovery. JSM Chem. 2016;4(3):1029.
11. James JP, Bhat, KI, More UA, Joshi S. Med Chem Res. 2018;27:546. https://doi.org/10.1007/s00044-017-2081-9.
12. Mukesh B, Rakesh K. Molecular docking: a review. International Journal of Research in Ayurveda and Pharmacy. 2011;2(6):1746-51.
13. Kalva S, Agrawal N. Structure based Pharmacophore Modeling and Molecular Docking Studies of Kaposi’s Sarcoma-Associated Herpes Virus (KSHV) Protease – A Therapeutic Drug Target. Research J. Pharm. and Tech. 2019; 12(11):5177-81.
14. Xie F, Zhao H, Zhao L, Lou L, Hu Y. Synthesis and biological evaluation of novel 2, 4, 5-substituted pyrimidine derivatives for anticancer activity. Bioorganic and medicinal chemistry letters. 2009;19(1):275-8.
15. Giles D, Roopa K, Sheeba FR, Gurubasavarajaswamy PM, Divakar G, Vidhya T. Synthesis pharmacological evaluation and docking studies of pyrimidine derivatives. European journal of medicinal chemistry. 2012;58:478-84.
16. Murugan R, Arjunan R, Austin M, Belsen J, Vijin P, Tom S. Synthesis of 2-Substituted Pyrimidines and Evaluation of Its Pharmacological Activities. Research J. Pharm. and Tech. 2010: 3(1); 161-164.
17. Thirumurugan P, Mahalaxmi S, Perumal PT. Synthesis and anti-inflammatory activity of 3-indolyl pyridine derivatives through one-pot multi component reaction. Journal of chemical sciences. 2010;122(6):819-32.
18. Altaf AA, Shahzad A, Gul Z, Rasool N, Badshah A, Lal B, Khan E. A review on the medicinal importance of pyridine derivatives. Journal of Drug Design and medicinal chemistry. 2015;1(1):1-1.
19. Baviskar BA, Baviskar B, Shiradkar MR, Deokate UA, Khadabadi SS. Synthesis and antimicrobial activity of some novel. Benzimidazolyl chalcones. Eur J Chem. 2009;6:196–200.
20. Babasaheb PB, Sachin AP, Rajesh NG. Synthesis and biological evaluation of nitrogencontaining chalcones as possible anti-inflammatory and antioxidant agents. Bioorg Med Chem Lett. 2010;20:730–733.
21. Bhat KI, Kumar A, Kumar P, Riyaz EK. Synthesis and Biological Evaluation of Some Novel Pyrimidine Derivatives Derived from Chalcones. Research J. Pharm. and Tech. 2014: 7(9):995-998.
22. Do TH, Nguyen DM, Truong VD, Do THT, Le MT, Pham TQ, et al. Synthesis and selective cytotoxic activities on rhabdomyosarcoma and noncancerous cells of some heterocyclic chalcones. Molecules. 2016;21(3):329. https://doi.org/10.3390/molecules21030329
23. Zeni G, Nogueira CW, Panatieri RB, Silva DO, Menezes PH, Braga AL, et al. Synthesis and anti-inflammatory activity of acetylenic thiophenes. Tetrahedron Letters. 2001;42(45):7921-3.
24. Amr AG, Hegab MI, Ibrahiem AA, Abdulla MM. Synthesis and reactions of some fused oxazinone, pyrimidinone, thiopyrimidinone, and triazinone derivatives with a thiophene ring as analgesic, anticonvulsant, and antiparkinsonian agents. Monatshefte für Chemie/Chemical Monthly. 2003;134(10):1395-409.
25. Brault L, Migianu E, Néguesque A, Battaglia E, Bagrel D, Kirsch G. New thiophene analogues of kenpaullone: synthesis and biological evaluation in breast cancer cells. European journal of medicinal chemistry. 2005;40(8):757-63.
26. Shehab WS, Abdellattif MH, Mouneir SM. Heterocyclization of polarized system: synthesis, antioxidant and anti-inflammatory 4-(pyridin-3-yl)-6-(thiophen-2-yl) pyrimidine-2-thiol derivatives. Chemistry Central Journal. 2018;(1):68.
27. Schrödinger release 2019-1; Maestro, Schrödinger, New York, NY, 2019.
28. Schrödinger release 2019-1; QikProp, Schrödinger, LLC, New York, NY, 2019.
29. Schrödinger release 2019-1; Ligprep, Schrödinger, LLC,New York, NY, 2019.
30. Picot D, Loll PJ, Garavito RM. The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1. Nature. 1994; 367(6460):243.
31. Kurumbail RG, Stevens AM, Gierse JK, McDonald JJ, Stegeman RA, Pak JY, Gildehaus D, Penning TD, Seibert K, Isakson PC, Stallings WC. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature. 1996;384(6610):644-8.
32. Kawatkar S, Wang H, Czerminski R, Joseph-McCarthy D. Virtual fragment screening: an exploration of various docking and scoring protocols for fragments using Glide. J Comput. Aided. Mol. Des. 2009;23(8):527-39.
33. Kalirajan R, Pandiselvi M, Sankar S, Gowramma B. Molecular Docking Studies and In silico ADMET Screening of Some Novel Chalcone Substituted 9-Anilinoacridines as Topoisomerase II Inhibitors. SF J Pharm Anal Chem. 2018;1(1);1004.