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Current Drug Research Reviews

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ISSN (Print): 2589-9775
ISSN (Online): 2589-9783

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Research Article

An In-silico Approach: Design, Homology Modeling, Molecular Docking, MM/GBSA Simulations, and ADMET Screening of Novel 1,3,4-oxadiazoles as PLK1inhibitors

Author(s): Sindhya Malkaje, Mahendra Gowdru Srinivasa, Shridhar Deshpande N, Suharsha Navada and Revanasiddappa BC*

Volume 15, Issue 1, 2023

Published on: 20 October, 2022

Page: [88 - 100] Pages: 13

DOI: 10.2174/2589977514666220821203739

Price: $65

Abstract

Background: Breast cancer is the most commonly diagnosed and major cause of cancer-related deaths in women worldwide. Disruption of the normal regulation of cell cycle progression and proliferation are the major events leading to cancer. Human Polo-like Kinase 1 (PLK1) plays an important role in the regulation of cellular division. High PLK1 expression is observed in various types of cancer including breast cancer. 1,3,4-oxadiazoles are the fivemembered heterocycles, that serve as versatile lead molecules for designing novel anticancer agents and they mainly act by inhibiting various enzymes and kinases.

Objective: A novel series of 1,3,4-oxadiazole derivatives (A1-A26) were designed and subjected to an in-silico analysis against PLK1 enzyme (PDB ID:1q4k), targeting breast cancer.

Methods: The chemical structure of each compound (A1-26) was drawn using ChemDraw software. The 3D structure model of protein target (PDB ID:1q4k) was built using the SWISSMODEL server. Molecular docking simulation was performed to determine the designed compound’s probable binding mode and affinity towards the protein target (PDB ID:1q4k). The designed compounds were subjected to ADME screening, as well as Prime MM/GBSA simulations using Schrodinger suite 2020-4. Furthermore, the safety profile of compounds was examined through the OSIRIS property explorer program and the results were compared with the standard drugs, 5-fluorouracil and cyclophosphamide.

Results: Based on the binding affinity scores, the compounds were found selective to target protein 1q4k through hydrogen bonding and hydrophobic interactions. The compounds A11, A12, and A13 were found to have higher G scores and binding free energy values. The ADME screening results were also found to be within the acceptable range. Moreover, the in-silico toxicity prediction assessments suggest that all designed compounds have a low risk of toxicity, and have higher efficiency for the target receptor.

Conclusion: The study showed that the substitution of electron-donating groups at the various position of the aromatic ring, which is bonded at the second position of the substituted 1,3,4- oxadiazole nucleus resulted in compounds with good binding energy and G score compared to the standard drugs, and hence, they can be further developed as potent PLK1 enzyme inhibitors.

Keywords: Breast cancer, 1, 3, 4-oxadiazole derivatives, PLK1, In-silico Molecular Docking, ADME screening, MM/GBSA

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[1]
Sarkar S, Horn G, Moulton K, et al. Cancer development, progression, and therapy: An epigenetic overview. Int J Mol Sci 2013; 14(10): 21087-113.
[http://dx.doi.org/10.3390/ijms141021087] [PMID: 24152442]
[2]
Liu L, Kawashima M, Toi M. Breast cancer in global health: Beyond diversity and inequality. IJS Global Health 2020; 3(6): e32.
[http://dx.doi.org/10.1097/GH9.0000000000000032]
[3]
Hortobagyi GN, de la Garza Salazar J, Pritchard K, et al. The global breast cancer burden: Variations in epidemiology and survival. Clin Breast Cancer 2005; 6(5): 391-401.
[http://dx.doi.org/10.3816/CBC.2005.n.043] [PMID: 16381622]
[4]
Donizy P, Halon A, Surowiak P, Kaczorowski M, Kozyra C, Matkowski R. Augmented expression of Polo-like kinase 1 is a strong predictor of shorter cancer-specific overall survival in early stage breast cancer at 15-year follow-up. Oncol Lett 2016; 12(3): 1667-74.
[http://dx.doi.org/10.3892/ol.2016.4890] [PMID: 27602103]
[5]
Xie S, Xie B, Lee MY, Dai W. Regulation of cell cycle checkpoints by polo-like kinases. Oncogene 2005; 24(2): 277-86.
[http://dx.doi.org/10.1038/sj.onc.1208218] [PMID: 15640843]
[6]
Degenhardt Y, Lampkin T. Targeting Polo-like kinase in cancer therapy. Clin Cancer Res 2010; 16(2): 384-9.
[http://dx.doi.org/10.1158/1078-0432.CCR-09-1380] [PMID: 20068088]
[7]
Liu Z, Sun Q, Wang X. PLK1, a potential target for cancer therapy. Transl Oncol 2017; 10(1): 22-32.
[http://dx.doi.org/10.1016/j.tranon.2016.10.003] [PMID: 27888710]
[8]
Liu X, Erikson RL. Polo-like kinase (Plk)1 depletion induces apoptosis in cancer cells. Proc Natl Acad Sci USA 2003; 100(10): 5789-94.
[http://dx.doi.org/10.1073/pnas.1031523100] [PMID: 12732729]
[9]
Boström J, Hogner A, Llinàs A, Wellner E, Plowright AT. Oxadiazoles in medicinal chemistry. J Med Chem 2012; 55(5): 1817-30.
[http://dx.doi.org/10.1021/jm2013248] [PMID: 22185670]
[10]
Broughton HB, Watson IA. Selection of heterocycles for drug design. J Mol Graph Model 2004; 23(1): 51-8.
[http://dx.doi.org/10.1016/j.jmgm.2004.03.016] [PMID: 15331053]
[11]
Patel KD, Shraddha MP, Shyamali NP, Patel HD. Review of synthesis of 1,3,4-oxadiazole derivatives. Syn Comm 2014; 44: 1859-75.
[http://dx.doi.org/10.1080/00397911.2013.879901]
[12]
Nagaraj, Chaluvaraju KC, Niranjan MS, Kiran S. 1,3,4-Oxadiazole: A potent drug candidate with various pharmacological activities. Int J Pharm Pharm Sci 2011; 3(3): 9-16.
[13]
de Oliveira CS, Lira BF, Barbosa-Filho JM, Lorenzo JGF, de Athayde-Filho PF. Synthetic approaches and pharmacological activity of 1,3,4-oxadiazoles: A review of the literature from 2000-2012. Molecules 2012; 17(9): 10192-231.
[http://dx.doi.org/10.3390/molecules170910192] [PMID: 22926303]
[14]
Guex N, Peitsch MC. SWISS‐MODEL and the swiss‐Pdb viewer: An environment for comparative protein modeling. Electrophoresis 1997; 18(15): 2714-3.
[http://dx.doi.org/10.1002/elps.1150181505]
[15]
Bienert S, Waterhouse A, de Beer TA, et al. The SWISS-MODEL repository-new features and functionality. Nucleic Acids Res 2017; 45(D1): D313-9.
[http://dx.doi.org/10.1093/nar/gkw1132] [PMID: 27899672]
[16]
Biasini M, Bienert S, Waterhouse A, et al. SWISS-MODEL: Modelling protein tertiary and quaternary structure using evolutionary information. Nucleic Acids Res 2014; 42: W252-8.
[http://dx.doi.org/10.1093/nar/gku340] [PMID: 24782522]
[17]
Abdullahi M, Adeniji SE, Arthur DE, Haruna A. Homology modeling and molecular docking simulation of some novel imidazo[1,2-a]pyridine-3-carboxamide (IPA) series as inhibitors of Mycobacterium tuberculosis. J Genet Eng Biotechnol 2021; 19(1): 12.
[http://dx.doi.org/10.1186/s43141-020-00102-1] [PMID: 33474593]
[18]
Hollingsworth SA, Karplus PA. A fresh look at the Ramachandran plot and the occurrence of standard structures in proteins. Biomol Concepts 2010; 1(3-4): 271-8.
[http://dx.doi.org/10.1515/bmc.2010.022]
[19]
Subramaniyan V, Sekar R, Praveenkumar A, Selvam R. Molecular modeling studies of repandusinic acid as potent small molecule for hepatitis B virus through molecular docking and ADME analysis. Quant Biol 2019; 7(4): 302-12.
[http://dx.doi.org/10.1007/s40484-019-0179-4]
[20]
Prabhu S, Vijayakumar S, Manogar P, Maniam GP, Govindan N. Homology modeling and molecular docking studies on Type II diabetes complications reduced PPARγ receptor with various ligand molecules. Biomed Pharmacother 2017; 92: 528-35.
[http://dx.doi.org/10.1016/j.biopha.2017.05.077] [PMID: 28575810]
[21]
Chaudhary KK, Mishra N. Investigation of the interaction between chalcones with CT-DNA by molecular docking, ADMET and fluorescence spectroscopy. Proc Natl Acad Sci, India, Sect A Phys Sci 2017; 87(2): 195-206.
[http://dx.doi.org/10.1007/s40010-017-0346-9]
[22]
Desai N, Shihory N, Khasiya A, Pandit U, Khedkar V. Quinazoline clubbed thiazole and 1, 3, 4-oxadiazole heterocycles: Synthesis, characterization, antibacterial evaluation, and molecular docking studies. Phosphorus Sulfur Silicon Relat Elem 2021; 196(6): 569-77.
[http://dx.doi.org/10.1080/10426507.2021.1871732]
[23]
Potshangbam AM, Nandeibam A, Amom T, et al. An in-silico approach to identify potential medicinal plants for treating Alzheimer disease: A case study with acetylcholinesterase. J Biomol Struct Dyn 2022; 40(4): 1521-33.
[http://dx.doi.org/10.1080/07391102.2020.1828170] [PMID: 33021148]
[24]
Mahapatra RK, Behera N, Naik PK. Molecular modeling and prediction of binding mode and relative binding affinity of Art-Qui-OH with P. falciparum Histo-Aspartic Protease (HAP). Bioinformation 2012; 8(17): 827-33.
[http://dx.doi.org/10.6026/97320630008827] [PMID: 23139593]
[25]
Deshpande NS, Mahendra GS, Aggarwal NN, Gatphoh BF, Revanasiddappa BC. Insilico design, ADMET screening, MM-GBSA binding free energy of novel 1, 3, 4 oxadiazoles linked Schiff bases as PARP-1 inhibitors targeting breast cancer. Future J Pharm Sci 2021; 7(1): 1.
[http://dx.doi.org/10.1186/s43094-021-00321-4]
[26]
Puratchikody A, Sriram D, Umamaheswari A, Irfan N. 3-D structural interactions and quantitative structural toxicity studies of tyrosine derivatives intended for safe potent inflammation treatment. Chem Cent J 2016; 10(1): 24.
[http://dx.doi.org/10.1186/s13065-016-0169-9] [PMID: 27141229]
[27]
Madhavaram M, Nampally V, Gangadhari S, Palnati MK, Tigulla P. High-throughput virtual screening, ADME analysis, and estimation of MM/GBSA binding-free energies of azoles as potential inhibitors of Mycobacterium tuberculosis H37Rv. J Recept Signal Transduct Res 2019; 39(4): 312-20.
[http://dx.doi.org/10.1080/10799893.2019.1660895] [PMID: 31658859]
[28]
Laskowski RA, Furnham N, Thornton JM. The ramachandran plot and protein structure validation. In: Bansal M, Srinivasan N, Eds. Biomolecular Forms and Functions. Banagalore(India): World Scientific 2013; pp. 62-75.
[http://dx.doi.org/10.1142/9789814449144_0005]
[29]
Divyashri G, Krishna Murthy TP, Sundareshan S, et al. In silico approach towards the identification of potential inhibitors from Curcuma amada Roxb against H. pylori: ADMET screening and molecular docking studies. Bioimpacts 2021; 11(2): 119-27.
[http://dx.doi.org/10.34172/bi.2021.19] [PMID: 33842282]
[30]
Pedrosa LF, de Macedo WP, Furtado AC, et al. Synthesis, crystal structures, and in silico toxicity prediction of thienopyridine phosphoramidates. Synth Commun 2013; 43(24): 3373-86.
[http://dx.doi.org/10.1080/00397911.2013.786092]
[31]
Allec SI, Sun Y, Sun J, Chang CA, Wong BM. Heterogeneous CPU+ GPU-enabled simulations for DFTB molecular dynamics of large chemical and biological systems. J Chem Theory Comput 2019; 15(5): 2807-15.
[http://dx.doi.org/10.1021/acs.jctc.8b01239] [PMID: 30916958]
[32]
Fedorov DG, Li H, Mironov V, Alexeev Y. Computational methods for biochemical simulations implemented in GAMESS. In: Heifetz A, Eds. Quantum Mechanics in Drug Discovery. 1st ed, Newyork : Springer Science, 2020; pp. 123-42.
[http://dx.doi.org/10.1007/978-1-0716-0282-9_8]

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