HOMOLOGY MODELING AND IN SILICO DOCKING ANALYSIS OF HUMAN MITOCHONDRIAL THYMIDINE KINASE 2 USING GRID-BASED LIGAND DOCKING WITH ENERGETICS
Objective:Mitochondrial disorders linked to Thymidine Kinase 2 (TK2) deficiency is associated to long term treatment with antiviral nucleoside analogues such as AZT (AZidoThymidine). The accumulation of AZT-TP (AZidoThymidine-TriPhosphate) is suggested to affect DNA polymerase, resulting in mtDNA (mitochondrial DNA) depletion. Thus a potent and selective inhibitor for TK2 is essential to be predicted.
Methods: The human mitochondrial TK2was modeled usingModeller and the structure was evaluated using Ramachandran plot. The ligand molecule of both the derivatives of deoxythymidine and thioureawere optimized usingChemsketch and were further docked using GLIDE SchrÃ¶dinger package 2009.
Results: The docking results of both Deoxythymidine and Thiourea derivatives against the target TK2 were analyzed to find the ligands with good dock score and Glide energy. The ligands were selected and induced fit docking of both the derivatives were carried out and the interactions were observed usingPyMol.
Conclusion: The present study indicates that deoxythymidine derivatives interact significantly and hence serve as selective inhibitors against Human Mitochondrial TK2.
2. Priego M E, Karlsson A, Gago F; Camarasa MJ, Balzarini J, Perez P et al. Recent Advances in Thymidine Kinase 2 (TK2) Inhibitors and New Perspectives for Potential Applications. Current Pharmaceutical Design 2012;18(20):2981-2994(14).
3. Ren S,Liya W. Thymidine Kinase 2 Enzyme Kinetics Elucidate the Mechanism of Thymidine-Induced Mitochondrial DNA Depletion. Biochemistry 2014;53(39):6142â€“6150.
4. Eriksson,S, Munch-PB, Johansson K, Eklund H. Structure and function of cellular deoxyribonucleoside kinases. Cell Mol Life Sci 2002;59:1327-1346.
5. Al-Madhoun A.S.; Tjarks W.; Eriksson S. The role of Thymidine Kinases in the activation of pyrimidine nucleoside analogs. Mini Rev Med Chem 2004;4:341-350.
6. Saada A, Shaag A, Mandel H, Nevo Y, Eriksson S, Elpeleg O. Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy. Nat Genet 2001;29:342-344.
7. Lewis W, Dalakas M.C. Mitochondrial toxicity of antiviral drugs.Nat Med 1995;1:417-422.
8. Lewis W, Day B.J, Copeland W.C. Mitochondrial toxicity of NRTI antiviral drugs: An integrated cellular perspective. Nature Rev Drug Discovery 2003;2:812-822.
9. Sherine S L. Chan, William CC. DNA polymerase gamma and mitochondrial disease: understanding the consequence of POLG mutations. BiochimBiophysActa 2009; 1787(5):312â€“319.
10. Shrasti G, VijayLaxmi S, Brijendra S. Homology Modeling and Docking Studies of Neuraminidase Protein of Influenza a Virus (H1N1) virus With Select Ligand â€“ A Computer Aided Structure Based Drug Design. IJPSI 2013; 2(6):35-41.
11. Arun J, Vetrivel U, Samdani A, Manoharan S, Subramanian K, Perinkulam RD. In Silico Structure Prediction of Human Fatty Acid Synthaseâ€“ Dehydratase: A Plausible Model for Understanding Active Site Interactions. BioinformBiol Insights 2016;10:143â€“154.
12. Manimekalai R, Victoriya MS, Shoba G. In silico docking analysis of Carbazo;lealaloids from Murrayakoenigii against PP2A. Int J Pharm Bio Sci 2015; 6(1):(B)913 â€“ 928.
13. Dhurga K , Gunasekaran G , Senthilraja P , Manivel G, Stalin Ab Molecular Modeling and Docking Analysis of Pseudomonal Bacterial Proteins with Eugenol and its derivatives RJLBPCS 2016;2(1):40.
14. Jayaraman A, Jamil K, Kakarala KK. Homology Modelling and Docking Studies of Human a2-Adrenergic Receptor Subtypes. J ComputSciSystBiol (2013);6:136-149.
15. Hua-Jun Luo1 , Jun-Zhi Wang1 , Nian-Yu Huang1 , Wei-Qiao Deng2 and Kun Zou1 Induced-fit docking and virtual screening for 8-hydroxy-3-methoxy- 5H-pyrido [2,1-c] pyrazin-5-one derivatives as inducible nitric oxide synthase inhibitors J Chem Pharm. Res 2014;6(3):1187-1194.
16. Balakrishnan V, Subramani P, Ramasamy R, Devadasan V. Identification of natural inhibitors against angiotensin I converting enzyme for cardiac safety using induced fit docking and MM-GBSA studies. Pharmacogn Mag 2014;10(3):S639â€“S644.
The publication is licensed under CC By and is open access. Copyright is with author and allowed to retain publishing rights without restrictions.