Determination of the anti-polo like kinase 1 potential of novel derivatives of thiophene using oncoinformatics approach

Moaath Khaled Aljbreen,Sibhghatulla Shaikh,Amr Salah,Mohammed Mubarak Alrashidi,Syed Mohd Danish Rizvi

doi:10.4314/tjpr.v20i3.9

Moaath Khaled Aljbreen, Sibhghatulla Shaikh + Show 3 more

Open Access

https://doi.org/10.4314/tjpr.v20i3.9

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Abstract

    Purpose: To explore the anticancer mechanistic aspect of thiophene derivatives via targeting Polo like kinase 1 (PLK1). Methods: The PLK1 enzyme is primarily expressed in cancer cells, and blocking its active site is one of the plausible ways to target cancer. Thus, in the present study, the thiophene derivatives were tested against PLK1 by molecular docking approach. Results: Thiophene derivatives, named 8A, 8B and 14, exhibited better interactions with PLK1 active site than the positive control, doxorubicin. Molecular docking experiments revealed that 8A, 8B and 14 interacted efficiently with PLK1, and demonstrated binding energy and inhibition constant scores of ꞌ- 8.02 kcal/mol and 1.33 μMꞌ, ꞌ-8.65 kcal/mol and 0.454 μMꞌ and ꞌ-8.33 kcal/mol and 0.788 μMꞌ, respectively. In contrast, doxorubicin-PLK1 interaction had binding energy of -7.95 kcal/mol and inhibition constant of 2.75 μM. Conclusion: These results predict that thiophene derivatives 8A, 8B and 14 might exert anticancer effect by inhibiting PLK1 activity. Although, wet lab experiments are required to validate the data, however, these results may pave the way for the development of novel PLK1 inhibitors for anticancer therapy.   

Highlights

Cancer is a major health concern globally, and a major cause of mortality in the United States [1]
To explore the mechanistic aspects, we predicted the potential of thiophene derivatives against cancer specific target, i.e., Polo like kinase 1 (PLK1) in the present study
Leu59, Gly60, Lys61, Cys67, Ala80, Leu130, Glu131, Leu132, Cys133, Arg134, Arg136, and Phe183 residues of PLK1 was found to interact with compound 8A (Figure 1a); while compound 8B was found to interact with Leu59, Gly60, Lys61, Gly62, Ala65, Lys66, Cys67, Ala80, Lys82, Val114, Glu131, Leu132, Cys133, Arg134, Arg136, Phe183, and Asp194 residues of PLK1 (Figure 2a)

Summary

INTRODUCTION

Cancer is a major health concern globally, and a major cause of mortality in the United States [1]. Metastasis, recurrence and drug resistance are the factors that are associated with increased mortality rate Conventional chemotherapeutic agents, such as, antimitotic and antimetabolites drugs [2] are not adequate to control the majority of cancers, and frequently direct to drug-resistant. To explore the mechanistic aspects, we predicted the potential of thiophene derivatives against cancer specific target, i.e., PLK1 in the present study. Molinspiration property calculation tool (http://www.molinspiration.com/cgibin/properties) was employed to check the physicochemical properties of thiophene derivatives compounds. Various parameters such as topological polar surface area (TPSA), molecular weight, miLogP, the number of hydrogen bond donors, number of hydrogen bond acceptors, number of rotatable bonds, and violations of Lipinski’s rule of five [16] were estimated using Molinspiration tool. To determine the hydrogen and hydrophobic interactions between important amino acid residues of PLK1 with thiophene derivatives the ‘thiophene derivatives-PLK1’complexes were analyzed by LIGPLOT+ Version v.2.1

RESULTS

DISCUSSION

CONCLUSION

Conflict of interest