IN-SILICO EVALUATION OF BINDING INTERACTION AND ADME PROPERTIES OF NOVEL 5-(THIOPHEN-2-YL)-1,3,4-OXADIAZOLE-2-AMINE DERIVATIVES AS ANTI-PROLIFERATIVE AGENTS

Authors

  • YOUSEF SABAH ALI Department of Pharmaceutical Chemistry, College of Pharmacy, Mustansiriyah University, Baghdad, Iraq
  • MONTHER FAISAL MAHDI Department of Pharmaceutical Chemistry, College of Pharmacy, Mustansiriyah University, Baghdad, Iraq
  • BASMA M. ABD RAZIK Department of Pharmaceutical Chemistry, College of Pharmacy, Mustansiriyah University, Baghdad, Iraq

DOI:

https://doi.org/10.22159/ijap.2023v15i1.46488

Keywords:

Drug design, molecular docking, oxadiazole derivatives, anti-proliferative

Abstract

Objective: The objective of this research was the virtual design of nine novel 1,3,4-oxadiazole derivatives and evaluating their antiproliferative activity as potential cyclin-dependent kinase 2 (CDK-2) inhibitors, which is a major component in cell cycle and proliferation.

Methods: CDK-2 structure, PDB ID, 2R3J, co-crystallized with ligand SCJ from protein data bank was chosen to be docked with a series of nine 5-(thiophen-2-yl)-1,3,4-oxadiazol-2-amine derivatives to evaluate their abilities as potential anti-proliferative agents using Glide software (Maestro 11.4) one of Schrodinger software (Schrodinger, 2018). In addition, the pharmacokinetic properties of these derivatives were evaluated using the Swiss-ADME web tool.

Results: Molecular modeling proposed that these 1,3,4-oxadiazole derivatives have powerful binding interaction with the active binding site of CDK-2 protein. In this article, two molecules have been observed as the most effective as they have docking scores of (-10.654 and -10.169 kcal/mol) respectively, whereas the binding score of the reference ligand was (-9.919 Kcal/mol) and most of the derivatives have fulfilled the Swiss-ADME parameters as potential orally active compounds.

Conclusion: Novel 1,3,4-oxadiazole derivatives had shown promising results to be considered as lead compounds for developing new anti-proliferative agents as two compounds (P-1 and P-5) exhibit better docking score at 2R3J active site than the reference ligand with further biological and pharmacological evaluation required.

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References

Bhutadiya VL, Mistry KN. A Review on bioactive phytochemicals and it’s mechanism on cancer treatment and prevention by targeting multiple cellular signaling pathways. Int J Pharm Pharm Sci. 2021 Dec 1;13(12):15–9.

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. 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.

Chen J, Pang L, Wang W, Wang L, Zhang JZH, Zhu T. Decoding molecular mechanism of inhibitor bindings to CDK2 using molecular dynamics simulations and binding free energy calculations. J Biomol Struct Dyn. 2020 Mar 3;38(4):985–96.

Peyressatre M, Prével C, Pellerano M, Morris MC. Targeting cyclin-dependent kinases in human cancers: From small molecules to peptide inhibitors. Cancers (Basel). 2015 Jan 23;7(1):179-237.

Phoujdar MS, Aland GR. Molecular docking study on 1H-(3,4d) pyrazolo-pyrimidines as cyclin dependant kinase (CDK2) inhibitors. Int J Curr Pharm Res. 2016 Dec 31;9(1):94.

Housman G, Byler S, Heerboth S, Lapinska K, Longacre M, Snyder N, Sarkar S. Drug resistance in cancer: An overview. Cancers (Basel). 2014 Sep 5;6(3):1769-92.

Kavitha S, Gnanavel S, Kannan K. Biological aspects of 1,3,4-oxadiazole derivatives. Asian J Pharm Clin Res. 2014;7(4):11-20.

Boström J, Hogner A, Llinàs A, Wellner E, Plowright AT. Oxadiazoles in medicinal chemistry. J Med Chem. 2012 Mar 8;55(5):1817–30.

Yahya TA, Abdullah JH. Synthesis of some 2,3-dihydro-1,3,4-oxadiazoles and 4,5-dihydro-1,2,4-triazoles as anticancer agents. Int J Pharm Pharm Sci. 2020 Jun 25;12(8):92–9.

Ghazi YAF, Mahdi MF, Dawood AH. Theoretical drug design, molecular docking and ADME study of new 1,3,4-oxadiazole derivatives: promising anticancer agents against both breast and lung cancers. Egypt J Chem. 2021 Nov 1;64(11):6269–83.

Kotaiah Y, Harikrishna N, Nagaraju K, Venkata Rao C. Synthesis and antioxidant activity of 1,3,4-oxadiazole tagged thieno[2,3-d]pyrimidine derivatives. Eur J Med Chem. 2012 Dec;58:340–5.

Jwaid MM, Ali KF, Abd-alwahab MH. Synthesis, antibacterial study and ADME evaluation of novel isonicotinoyl hydrazide derivative containing 1,3,4-oxadiazole moiety. Al Mustansiriyah Journal of Pharmaceutical Sciences. 2020 Dec 1;20(4):113-21.

Omran SM, Abd Razik BM, Mahdi MF. Density functional theory and molecular modeling studies of new 4-(Furan-2-yl) thiazol-2-amine derivatives as cyclooxygenase inhibitors. Egypt J Chem. 2021 Sep 1;64(9):4833–41.

Ezzat MO, Razik BMA. Molecular modelling design and opioid binding affinity evaluation of new 4-chromanone derivatives. J Microbiol Biotech Food Sci. 2021;10(4):531–5.

Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017 Mar 3;7:42717.

Sliwoski G, Kothiwale S, Meiler J, Lowe EW. Computational methods in drug discovery. Pharmacol Rev. 2013 Dec 31;66(1):334-95.

Alimbetov D, Askarova S, Umbayev B, Davis T, Kipling D. Pharmacological targeting of cell cycle, apoptotic and cell adhesion signaling pathways implicated in chemoresistance of cancer cells. Int J Mol Sci. 2018 Jun 6;19(6):1690.

Leal-Esteban LC, Fajas L. Cell cycle regulators in cancer cell metabolism. Biochim Biophys Acta Mol Basis Dis. 2020 May 1;1866(5):165715.

Roskoski R. Cyclin-dependent protein kinase inhibitors including palbociclib as anticancer drugs. Pharmacol Res. 2016 May;107:249-275.

Bhatt P, Sen A, Jha A. Design and ultrasound assisted synthesis of novel 1,3,4-oxadiazole drugs for anti-cancer activity. ChemistrySelect. 2020 Mar 20;5(11):3347–54.

Santosh R, Prabhu A, Selvam MK, Krishna PM, Nagaraja GK, Rekha PD. Design, synthesis, and pharmacology of some oxadiazole and hydroxypyrazoline hybrids bearing thiazoyl scaffold: antiproliferative activity, molecular docking and DNA binding studies. Heliyon. 2019 Feb 1;5(2):1255.

Liang JW, Wang MY, Wang S, Li SL, Li WQ, Meng FH. Identification of novel CDK2 inhibitors by a multistage virtual screening method based on SVM, pharmacophore and docking model. J Enzyme Inhib Med Chem. 2020 Jan 1;35(1):235–44.

Klebe G. Virtual ligand screening: strategies, perspectives and limitations. Drug Discov Today. 2006 Jul;11(13-14):580-94.

Prasanna S, Doerksen RJ. Topological Polar Surface Area: A Useful Descriptor in 2D-QSAR Curr Med Chem. 2009;16(1):21-41.

Palm K, Stenberg P, Luthman K, Artursson P. Polar molecular surface properties predict the intestinal absorption of drugs in humans. Pharm Res. 1997 May;14(5):568-71

Benet LZ, Hosey CM, Ursu O, Oprea TI. BDDCS, the Rule of 5 and drugability. Adv Drug Deliv Rev. 2016 Jun 1;101:89-98.

Published

21-11-2022

How to Cite

ALI, Y. S., MAHDI, M. F., & RAZIK, B. M. A. (2022). IN-SILICO EVALUATION OF BINDING INTERACTION AND ADME PROPERTIES OF NOVEL 5-(THIOPHEN-2-YL)-1,3,4-OXADIAZOLE-2-AMINE DERIVATIVES AS ANTI-PROLIFERATIVE AGENTS. International Journal of Applied Pharmaceutics, 15(1). https://doi.org/10.22159/ijap.2023v15i1.46488

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