Synthesis, structural characterization, DFT calculations, molecular docking, and molecular dynamics simulations of a novel ferrocene derivative to unravel its potential antitumor activity

Abstract

In this article, we describe a set of subsequent five-steps chemical reactions to synthesize a ferrocene derivative named 1-(5-(diphenylphosphaneyl)cyclopenta-1,3-dien-1-yl)ethyl)imino)-1,3-dihydroisobenzofuran-5-yl)methanol (compound 10). Structural characterization of 10 and its intermediate products was also performed and reported to attest to their formation. A molecular docking study was performed to propose the novel synthesized ferrocene derivative (10) as a potential antitumor candidate targeting the mitogen-activated protein (MAP) kinases interacting kinase (Mnk) 1. The computed docking score of (10) at −9.50 kcal/mol compared to the native anticancer staurosporine at −8.72 kcal/mol postulated a promising anticancer activity. Also, molecular dynamics (MD) simulations were carried out for 500 ns followed by MM-GBSA-binding free energy calculations for both the docked complexes of ferrocene and staurosporine to give more deep insights into their dynamic behavior in physiological conditions. Furthermore, DFT calculations were performed to unravel some of the physiochemical characteristics of the ferrocene derivative (10). The quantum mechanics calculations shed the light on some of the structural and electrochemical configurations of (10) which would open the horizon for further investigation.

Highlights

• The synthesis of a ferrocene derivative named 1-(5-(diphenylphosphaneyl)cyclopenta-1,3-dien-1-yl)ethyl)imino)-1,3-dihydroisobenzofuran-5-yl)methanol (compound 10) was described.

• Structural characterizations of ferrocene derivative (10) and its intermediate products were also performed.

• DFT calculations, molecular docking, molecular dynamics, and MM-GBSA calculations were carried out.

• Computational studies revealed the antitumor potential of ferrocene derivative (10) through targeting and inhibiting mitogen-activated protein (MAP) kinases interacting kinase (Mnk) 1.

Communicated by Ramaswamy H. Sarma

Keywords:

• Ferrocene
• synthesis
• molecular docking
• molecular dynamics
• MM-GBSA
• DFT calculations

Author contributions

Conceptualization: Mohamed M. Hammoud and Ahmed A. Al-karmalawy; Data curation: Mohamed M. Hammoud, Muhammad Khattab, Marwa Abdel-Motaal, Johan Van der Eycken, Radwan Alnajjar, Hamada S. Abulkhair, and Ahmed A. Al‐Karmalawy; Formal Analysis: Mohamed M. Hammoud, Muhammad Khattab, Marwa Abdel-Motaal, Hamada S. Abulkhair, and Ahmed A. Al‐Karmalawy; Funding acquisition: Mohamed M. Hammoud and Ahmed A. Al-Karmalawy; Investigation: Marwa Abdel-Motaal and Ahmed A. Al-Karmalawy; Methodology: Mohamed M. Hammoud, Muhammad Khattab, Marwa Abdel-Motaal, Johan Van der Eycken, and Ahmed A. Al‐Karmalawy; Project administration: Ahmed A. Al-Karmalawy; Resources: Mohamed M. Hammoud and Ahmed A. Al-Karmalawy; Software: Muhammad Khattab, Radwan Alnajjar, and Ahmed A. Al‐Karmalawy; Supervision: Ahmed A. Al-Karmalawy; Validation: Muhammad Khattab and Ahmed A. Al-Karmalawy; Visualization: Muhammad Khattab and Ahmed A. Al-Karmalawy; Writing – original draft: Mohamed M. Hammoud, Muhammad Khattab, Marwa Abdel-Motaal, Johan Van der Eycken, and Ahmed A. Al‐Karmalawy; Writing – review & editing: Muhammad Khattab, Marwa Abdel-Motaal, Hamada S. Abulkhair, and Ahmed A. Al‐Karmalawy. All authors approved the final version of the manuscript.

Disclosure statement

The authors declare that there is no conflict of interest.

Funding

The author(s) reported there is no funding associated with the work featured in this article.

Author declaration

We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property. We understand that the Corresponding Author is the sole contact for the Editorial process. He is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs. We confirm that we have provided current, correct email address which is accessible by the Corresponding Author and which has been configured to accept emails from: [email protected]

Mohamed M. Hammoud: [email protected]

Muhammad Khattab: [email protected]

Marwa Abdel-Motaal: [email protected]

Johan Van der Eycken: [email protected]

Radwan Alnajjar: [email protected]

Hamada S. Abulkhair: [email protected]