DESIGN FOR THE COLON CANCER INHIBITORS TARGETING THYMIDYLATE KINASE BY USING INSILICO STUDIES

MOHD ABDUL BAQI; KOPPULA JAYANTHI; RAMAN RAJESHKUMAR

doi:10.22159/ijap.2024v16i3.50079

Authors

MOHD ABDUL BAQI Department of Pharmaceutical Biotechnology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Nilgiris, Tamil Nadu, India https://orcid.org/0009-0000-3711-3568
KOPPULA JAYANTHI Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Nilgiris, Tamil Nadu, India https://orcid.org/0009-0003-9358-4278
RAMAN RAJESHKUMAR Department of Pharmaceutical Biotechnology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Nilgiris, Tamil Nadu, India

DOI:

https://doi.org/10.22159/ijap.2024v16i3.50079

Keywords:

Thymidylate kinase (TMK), Molecular docking, Molecular dynamics simulations, MM-GBSA, HTVS, ADME, cancer, HaTMK

Abstract

Objective: Thymidylate Kinase (TMK) plays a crucial role in bacterial DNA synthesis by catalyzing the phosphorylation of Deoxythymidine Monophosphate (dTMP) to form Deoxythymidine Diphosphate (dTDP). Consequently, this enzyme emerges as a promising target for developing novel anti-cancer drugs. However, no anti-cancer drugs have been reported for this target until now.

Methods: Ligands obtained from Benzylidene derivatives were examined for their potency by using molecular docking by glide module, Qikprop screening of Absorption, Distribution, Metabolism, and Excretion (ADME) study, and prime Molecular Mechanics in Generalized Bond Surface Area study (MM-GBSA) by binding free energy. Hereafter, a Molecular Dynamic (MD) simulation was performed at 100 ns to assess the stability of the potential ligand as a Human TMK (HaTMK) inhibitor.

Results: These ten molecules showed good binding affinity and hydrogen and hydrophobic bond interactions with Arg150, Phe42, and Phe72 in the HaTMK enzyme (PDB id: 1E2D). Among them, trichloro-6-(((4-hydroxyphenyl)imino)methyl)phenol molecule had a high XP-docking score of (−7.87 kcal/mol), based on extra-precision data. Prime MM-GBSA studies also showed promising binding affinities i.e., ΔBind (-34.59 kcal/mol), ΔLipo (-13.92 kcal/mol), and ΔVdW (-34.42 kcal/mol). Arg76 and Phe72 residues maintained constant interactions with the ligand during Molecular Dynamics (MD) simulation. This ligand showed a potential binding affinity for the TMK target.

Conclusion: The trichloro-6-(((4-hydroxyphenyl)imino)methyl)phenol ligand has active sites, namely benzene ring, benzylidene, and oxygen group, which actively participate in interaction with the protein of HaTMK, thus indicating good potential activity as the inhibitor of HaTMK to treat colon cancer.

Downloads

Download data is not yet available.

References

Shewach DS, Kuchta RD. Introduction to cancer chemotherapeutics. Chem Rev. 2009 Jul 8;109(7):2859-61. doi: 10.1021/cr900208x, PMID 19583428.

Hassanpour SH, Dehghani M. Review of cancer from the perspective of molecular. J Cancer Res Pract. 2017;4(4):127-9. doi: 10.1016/j.jcrpr.2017.07.001.

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021 May;71(3):209-49. doi: 10.3322/caac.21660, PMID 33538338.

Labianca R, Beretta G, Gatta G, de Braud F, Wils J. Colon cancer. Crit Rev Oncol Hematol. 2004;51(2):145-70. doi: 10.1016/j.critrevonc.2004.03.003, PMID 15276177.

Munier Lehmann H, Chaffotte A, Pochet S, Labesse G. Thymidylate kinase of mycobacterium tuberculosis: a chimera sharing properties common to eukaryotic and bacterial enzymes. Protein Sci. 2001 Jun;10(6):1195-205. doi: 10.1110/ps.45701, PMID 11369858.

Ostermann N, Schlichting I, Brundiers R, Konrad M, Reinstein J, Veit T. Insights into the phosphoryl transfer mechanism of human thymidylate kinase gained from crystal structures of enzyme complexes along the reaction coordinate. Structure. 2000;8(6):629–42. doi: 10.1016/s0969-2126(00)00149-0, PMID 10873853.

Kotaka M, Dhaliwal B, Ren J, Nichols CE, Angell R, Lockyer M. Structures of S. aureus thymidylate kinase reveal an atypical active site configuration and an intermediate conformational state upon substrate binding. Protein Sci. 2006;15(4):774-84. doi: 10.1110/ps.052002406, PMID 16522804.

Ostermann N, Schlichting I, Brundiers R, Konrad M, Reinstein J, Veit T. Insights into the phosphoryltransfer mechanism of human thymidylate kinase gained from crystal structures of enzyme complexes along the reaction coordinate. Structure. 2000;8(6):629-42. doi: 10.1016/s0969-2126(00)00149-0, PMID 10873853.

Lingaraju S, Venkatesh L. Effect of 2 w yoga and meditation on emotional quotient. Natl J Physiol Pharm Pharmacol. 2018;8(9):1269-70. doi: 10.5455/njppp.2018.8.0416408052018.

Blanco Jerez LM, Rangel Oyervides LD, Gomez A, Jimenez Perez VM, Munoz Flores BM. Electrochemical metallization with Sn of (E)-4-((4-nitrobenzylidene) amino)phenol in non-aqueous media: characterization and biological activity of the organotin compound. Int J Electrochem Sci. 2016;11(1):45-53. doi: 10.1016/S1452-3981(23)15825-1.

James JP, Aiswarya TC, Priya S, Jyothi D, Dixit SR. Structure-based multitargeted molecular docking analysis of pyrazole-condensed heterocyclics against lung cancer. Int J App Pharm. 2021;3(6):157-69. doi: 10.22159/ijap.2021v13i6.42801.

Dar AM, Mir S. Molecular docking: approaches, types, applications and basic challenges. J Anal Bioanal Tech. 2017;8(2):1-3. doi: 10.4172/2155-9872.1000356.

Sastry GM, Adzhigirey M, Day T, Annabhimoju R, Sherman W. Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aided Mol Des. 2013 Mar;27(3):221-34. doi: 10.1007/s10822-013-9644-8, PMID 23579614.

Sukumaran S, MM, SS, BA, SS S ST. In silico analysis of acridone against TNF-α and PDE4 targets for the treatment of psoriasis. Int J Res Pharm Sci. 2020 Dec 18;11(4):7790-8.

Dunkel M, Fullbeck M, Neumann S, Preissner R. Super natural: a searchable database of available natural compounds. Nucleic Acids Res. 2006;34:D678-83. doi: 10.1093/nar/gkj132, PMID 16381957.

Jacobson MP, Pincus DL, Rapp CS, Day TJF, Honig B, Shaw DE. A hierarchical approach to all‐atom protein loop prediction. Proteins. 2004 May;55(2):351-67. doi: 10.1002/prot.10613, PMID 15048827.

Dhawale S, Gawale S, Jadhav A, Gethe K, Raut P, Hiwarale N. In silico approach targeting polyphenol as Fabh inhibitor in bacterial infection. Int J Pharm Pharm Sci. 2022;14(11):25-30. doi: 10.22159/ijpps.2022v14i11.45816.

Martyna GJ, Tuckerman ME, Tobias DJ, Klein ML. Explicit reversible integrators for extended systems dynamics. Mol Phys. 1996;87(5):1117-57. doi: 10.1080/00268979600100761.

Guo Z, Mohanty U, Noehre J, Sawyer TK, Sherman W, Krilov G. Probing the α‐helical structural stability of stapled p53 peptides: molecular dynamics simulations and analysis. Chem Biol Drug Des. 2010 Apr;75(4):348-59. doi: 10.1111/j.1747-0285.2010.00951.x, PMID 20331649.

Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG. A smooth particle mesh Ewald method. J Chem Phys. 1995;103(19):8577-93. doi: 10.1063/1.470117.

Harder E, Damm W, Maple J, Wu C, Reboul M, Xiang JY. OPLS3: a force field providing broad coverage of drug-like small molecules and proteins. J Chem Theory Comput. 2016 Jan 12;12(1):281-96. doi: 10.1021/acs.jctc.5b00864, PMID 26584231.

Martyna GJ, Tobias DJ, Klein ML. Constant pressure molecular dynamics algorithms. J Chem Phys. 1994 Sep 1;101(5):4177-89. doi: 10.1063/1.467468.

Badavath VN, Sinha BN, Jayaprakash V. Design, in silico docking and predictive ADME properties of novel pyrazoline derivatives with selective human MAO inhibitory activity. Int J Pharm Pharm Sci. 2015;7:277-82.

Chen YH, Hsu HY, Yeh MT, Chen CC, Huang CY, Chung YH. Chemical inhibition of human thymidylate kinase and structural insights into the phosphate binding loop and ligand-induced degradation. J Med Chem. 2016;59(21):9906-18. doi: 10.1021/acs.jmedchem.6b01280, PMID 27748121.

Ajmal A, Mahmood A, Hayat C, Hakami MA, Alotaibi BS, Umair M. Computer-assisted drug repurposing for thymidylate kinase drug target in monkeypox virus. Front Cell Infect Microbiol. 2023;13:1159389. doi: 10.3389/fcimb.2023.1159389, PMID 37313340.