MOLECULAR DOCKING STUDY OF SIX PYRIMIDINE DERIVATIVES AS EGFR (EPIDERMAL GROWTH FACTOR RECEPTOR) AND CA IX (CARBONIC ANHYDRASE IX) INHIBITOR

SHIKHA SHARMA; V. J. SHUKLA

doi:10.22159/ijpps.2019v11i3.31183

Authors

SHIKHA SHARMA Department of Pharmaceutical Chemistry, IPGT and RA, Gujarat Ayurved University, Jamnagar
V. J. SHUKLA Department of Pharmaceutical Chemistry, IPGT and RA, Gujarat Ayurved University, Jamnagar

DOI:

https://doi.org/10.22159/ijpps.2019v11i3.31183

Keywords:

Docking, Pyrimidine, Pyrx, Molecule

Abstract

Objective: The present study was carried out to discover whether these pyrimidine derivatives have the potential to be used as epidermal growth factor receptor (EGFR) and carbonic anhydrase (CA) IX inhibitors through structure-based in silico study.

Methods: Docking was performed on 6 pyrimidine analogs; cetuximab and curcumin were taken as reference drug. The structure of the target protein retrieved from the RCSB Protein databank and the protein-ligand docking was performed using Pyrx AutoDock wizard with MGL tools 1.5.6 by using Lamarckian algorithm.

Results: All the compounds have shown lower binding energy and inhibition constant (Ki) value than reference drug cetuximab and curcumin. Out of the 6 inhibitors analyzed vkh has shown minimum binding energy against the target protein EGFR and CA IX respectively. Smaller Ki value shows stronger interaction. The scoring value of the interaction of vkh i. e-10.74 and-9.93 Kcal/mol and Ki 13.17ɳM and 53.04ɳM against the target protein EGFR and CA IX respectively while the reference drug cetuximab has shown binding energy-6.09 Kcal/mol with Ki value 34.44 µM and curcumin has shown binding energy-6.02 kcal/mol with Ki value 38.60 µM.

Conclusion: It can be concluded that the molecule vkh could have potential to be used as an EGFR inhibitor and CA IX inhibitor.

Downloads

Download data is not yet available.

References

Lagoja IM. Pyrimidine as the constituent of natural biologically active compounds review. Chem Biod 2005;2:1-501.

Yerragunta V, Patil P, Anusha V, Swamy TK, Suman D, Samhitha T. Pyrimidine and its biological activity: a review. Pharmatherapeutica 2013;1:39-44.

Desai K, Patel R, Chikhalia K. Synthesis of pyrimidine-based thiazolidines and azetidinones: antimicrobial and antitubercular agent. Indian J Chem 2006;45:773-8.

Choudhary A, Verma P, Dudhi R. Significant antimicrobial activity of novel pyrimidine derivative. Elic Pharma’s 2012;45:7956-63.

Said S, Amr AE, Nermien MS, Abdalla MM. Analgesic, anti convalescent and anti-inflammatory activities of some synthesized benzodiazepines, triazolo pyrimidines, and bisimide derivatives. Eur J Med Chem 2009;44:4787-92.

Kai D, Zhang Z, Chen Y, Yan XJ, Zou LJ, Wangand YX, et al. Synthesis antibacterial and antitubercular activities of some 5-H-Thiazolo[3,2a]pyrimidine-5-onesand sulphonic acid derivative. Molecular 2015;20:16419-34.

Sun L, Wu J, Zhang L, Luo M, Sun D. Synthesis and antifungal activities of some novel pyrimidine derivatives. Molecular 2011;16:5618-28.

El-zahar MI, Somaia S, Karim A, Haiba ME, Khedr MA. Synthesis, antitumor activity and molecular docking study of novel benzofuran-2yl pyrazole pyrimidine derivatives. Drug Res 2011;68:357-73.

Ghorab MM, Alsaid MS. Anticancer activity of some novel thieno [2, 3-d] pyrimidine derivatives. Bio Res 2016;7:110-5.

Kim, Lee DC, Yang YR, Shin BS, Kim KJ, Chung DJ, et al. Synthesis and biological evaluations of pyrazolo[3,4-d]pyrimidines as cyclin-dependent kinase 2 inhibitors. Eur J Med Chem 2003;38:525–32.

Schenone S, Brullo C, Bruno O, Bondavalli F, Mosti L, Maga G, et al. Synthesis, biological evaluation and docking studies of 4-amino substituted 1H-pyrazolo[3,4-d]pyrimidines. Eur J Med Chem 2008;43:2665–76.

Schenone S, Bruno O, Bondavalli F, Ranise A, Mosti L, Menozzi G, et al. 1-(2-Chloro-2-phenylethyl)6-methylthio-1H-pyrazolo[3,4-d]pyrimidines-4-amino substituted and their biological evaluation. Eur J Med Chem 2004;39:153–60.

Supuran CT. Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discovery 2008;7:168-81.

Partanen, Epidermal growth factor and transforming growth factor-alpha in the development of Epithelial-mesenchymal organs of the mouse. Curr Top Dev Biol 1990;24:31–55.

Supuran CT. Inhibition of carbonic anhydrase IX as a novel anticancer mechanism. World J Clin Onc 2012;3:98-103.

E Adamson. Developmental activities of the epidermal growth factor receptor. Curr Top Dev Biol 1990;24:1–29.

https://en.wikipedia.org/wiki/Carbonic_anhydrase. [Last accessed on 02 Oct 2018]

Jaikumar K, Sheik NM, John WW, Deventhiran M, Babu A, Anand D, et al. In silico docking analysis of bioactive compounds from Calophyllum inophyllum L. leaf extract against epidermal growth factor receptor (EGFR) protein. Asian J Pharm Clin Res 2017;10:214-9.

Harsh B, Nidhi B, Toraskar MP. Study of binding interactions of human carbonic anhydrase XII. Int J Curr Pharm Res 2017;9:118-25.

Ade A, Hendri A, Fadilah, Anton B, Hiroki T, Kiyomi K. Design and screening of gallic acid derivatives as inhibitors of malarial dihydrofolate reductase by in silico study. Asian J Pharm Clin Res 2017;10:330-4.

Saptarini NM, Sitorus EY, Levita J. Structure-based in silico study of 6-gingerol, 6-ghogaol, and 6-paradol, active compounds of ginger (Zingiber officinale) as COX-2 inhibitors. Int J Chem 2013;5:1-18.