Research Article
Evaluation of drug candidature: In silico ADMET, binding interactions with CDK7 and normal cell line studies of potentially anti-breast cancer enamidines

https://doi.org/10.1016/j.compbiolchem.2019.107124Get rights and content

Highlights

  • In silico ADMET of novel series of potentially anti-breast cancerous enamidines.

  • Good drug likeliness and bioactivity scores of synthesized enamidines.

  • Molecular docking of four lead molecules 4a-c and 4h with CDK7.

  • To develop better CDK7 inhibitors.

  • Low toxicity on vero cells.

Abstract

We have recently explored novel class of potentially anti-breast cancer active enamidines in which four molecules 4a-c and 4h showed higher anticancer activity compared to standard drug doxorubicin. As a part of extension of this work, we have further evaluated in silico cheminformatic studies on bioactivity prediction of synthesized series of enamidines using mole information. The normal cell line study of four lead compounds 4a-c and 4h against African green monkey kidney vero strain further revealed that the compounds complemented good selectivity in inhibition of cancer cells. The in silico bioactivity and molecular docking studies also revealed that the compounds have significant interactions with the drug targets. The results reveal that enamidine moieties are vital for anti-breast cancer activity as they possess excellent drug-like characteristics, being potentially good inhibitors of cyclin dependent kinases7 (CDK7).

Introduction

Breast cancer is predominantly encountered cancer in women in United States and other developing countries. It is the fifth most common cause of cancer related deaths in females (American Cancer Society, 2017). Current chemotherapeutic options for breast cancer include cytotoxic drugs such as tamoxifen, paclitaxel, docetaxel etc. most of which have serious side effects (Mahdavi and Moreau, 2016; Zeichner et al., 2016). The complex, heterogeneous biomolecular profile of breast cancer and acquired drug resistance have reduced the therapeutic efficacy of currently used anti-breast cancer agents (Cole, 2000). Another major clinical obstacle for cytotoxic anticancer agents is their toxicity as they exhibit a narrow therapeutic index between the required dose for desired antitumor effect and thereby resultant unacceptable toxicity. Moreover, toxicity of cytotoxic agents is realized prior than the desired anticancer activity, so, toxic effects express a major endpoint for pharmacodynamic studies. Knowledge of the toxicity of anticancer lead molecules constitutes a pre-requirement before modelling for pharmacodynamics (Peyressatre et al., 2015). These concerns have stimulated researchers to synthesize novel chemical architectures with better cytotoxic profiles targeting specific biological target (Raghi et al., 2018).

The Key players cyclin dependent kinases (CDKs) have significant contribution in cancer growth and progression which makes them a putative target for novel clinical interventions. CDKs are master controllers of the cell cycle and require discrete protein partner cyclin for its biological functioning. The action of kinases is controlled by periodic synthesis and degradation of positive regulatory cyclins, negative regulators and cyclin dependent kinase inhibitory molecules. Dysregulation of these events is a major factor in tumorigenesis of variety of malignancies (Lapenna and Giordano, 2009; Xua et al., 2014; Pisu et al., 2015; Arba et al., 2017). The loss of cell cycle control leading to unrestricted cell proliferation is a classic hallmark of cancer development and metastatic potential (Deshpande et al., 2005). Thus, targeting CDKs by developing small molecules as specific CDK inhibitors provides one of the convincing strategies in anticancer drug development. CDK7 complexes with cyclin H form CDK-activating-kinase (CAK) which phosphorylates, the other CDKs which serves as door keepers of the correct cell cycle progression (Ali et al., 2009; Fisher, 2005). The therapeutic importance of CDK7 makes it promising target for antitumor therapy as many CDK7 inhibitors like falvopiridol, roscovitine are in clinical trials (Mayer, 2015). Cyclin-dependent kinase inhibitors have recently developed as a reassuring therapeutic option in hormone dependent breast cancer as they appear to be well tolerated, with a manageable toxicity profile (Chatelut et al., 2003).

Based on aforementioned facts and in continuation of our work on Cu catalyzed multi-component reactions of tosyl azide, propargyl bromide and secondary amines leading to potentially active anti-breast cancer enamidines, we herein report in silico ADME studies, detailed binding interactions with CDK7 and normal cell line toxicity studies of lead compounds with a goal to evaluate drug candidature.

Section snippets

In silico evaluation of pharmacokinetic parameters and bioactivity scores

Advanced Chemistry Development (ACD) labs ChemSketch version 12.0 was used to generate two dimensional molecular structures and simplified molecular input line entry system (SMILES) notations of the synthesized enamidines. These structures were fed in Molinspiration Software in order to calculate various molecular properties and further to envisage the bioactivity scores of synthesized novel series of enamidines. The multiple biological targets for enamidines include kinase inhibitors, enzyme

Synthesis of enamidines (4 a-m)

The enamidines (4a-m) (Fig. 1) investigated in this work have been prepared by copper catalysed multi-component reaction of tosyl azide (1), propargyl bromide (2) and secondary amines (3a-m) (Scheme 1). All the compounds have been fully characterized on the basis of FT-IR, 1H NMR, 13C NMR and mass spectroscopy (Bansode et al., 2016).

Pharmacokinetics properties

Computational toxicology is a well-established discipline that incorporates in silico tools to support the prediction of toxicity and pharmacokinetic parameters

Conclusion

The molecular docking study ascertained that the enamidines can act as a putative inhibitor of CDK7 via strong hydrogen bonding interactions. The binding energy was found to be lesser pointing out the stable complex formation. These computational studies suggest that active enamidine molecules found to inhibit the functioning of CDK7 and responsible for the cell cycle arrest. Each compound exhibited apt pharmacological parameters such as hydrophobicity, good drug likeness and bioactive score

Declaration of Competing Interest

All authors declare that they have no potential conflict of interest.

Acknowledgements

One of the authors PB is thankful to University Grant Commission for providing teacher fellowship under Faculty Development Programme [FDP] during UGC XIIth plan, F. No. 38-08/14 (WRO). Authors are thankful to Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai for providing anti-cancer screening of the compounds.

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