DFT Studies and Acetylcholinesterase Inhibition Capacity Analysis of an Adamantane-Isothiourea Derivative via Docking and MD Calculations

Abstract

In this work, 4-bromobenzyl(Z)-N'-(adamantan-1-yl)-4-phenylpiperazine-1-carbothioimidate (4BAPC), an adamantane-isothiourea derivative, was studied through density functional theory (DFT) at the M06-2X/6 − 311 + G(2df,2p) level of theory, where its structural, vibrational, and quantum-chemical properties were comprehensively described. The analysis of the IR and Raman frequencies, with the help of potential energy distribution (PED) calculation, allowed the assignment of several characteristic vibrations that may be used in the identification of other adamantane-isothiourea derivatives. Solvation-free energy (SFE) calculations in water, ethanol, acetone, and chloroform were carried out, where acetone and chloroform showed the most negative values, −23.34 and −23.33 kcal/mol, respectively, suggesting that these two solvents better solubilize 4BAPC. Also, the SFE value in water, −10.49 kcal/mol, indicates good solubility in an aqueous medium. FMOs, MEP, ALIE surfaces, and Fukui indices calculations allowed to identify that the most reactive sites of 4BAPC comprise the aromatic rings and piperazine moiety. Acetylcholinesterase (AChE) inhibition capacity presented by 4BAPC was evaluated through molecular docking and molecular dynamics (MD) calculations. Docking binding affinity and MMPBSA binding energy showed, respectively, values of −9.2 and −29.954 kcal/mol, which indicates strong evidence for the AChE inhibitory potential by 4BAPC.

Keywords:

• Adamantane
• acetylcholinesterase
• DFT
• MD simulations
• docking

Ethical approval

We declare that this manuscript is original and that it was written by the authors and has not been published elsewhere. This study is not divided into other parts. The article reflects the research and analysis of the authors themselves truthfully and completely.

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All the authors agreed to participate in this research.

Consent for publication

All authors were responsible for ensuring the accuracy and integrity of all aspects of this work. All authors approved this version of the article.

Author contributions

All the authors contributed to the study conception and development of this manuscript. Lamya H. Al-Wahaibi and Ali A. El-Emam: Conceptualization, Synthesis of the compound, fund acquisition, conceiving the problem, spectroscopic analysis, software, manuscript preparation. Hanan M. Hassan: Formal analysis, Investigation, administration, Resources. Y. Sheena Mary and Y. Shyma Mary: Conceiving the problem, molecular docking and MD calculations, data analysis, correction, and writing final draft version. Renyer A. Costa, Emmanoel V. Costa, Victor L. Tananta: DFT calculations, data analysis, review, writing final draft version. Amal A El-Masry: Spectroscopic analysis, resources, supervision, manuscript preparation, and data analysis.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All data generated or analyzed during this study are included in this published article.

Additional information

Funding

This research was funded by Princess Nourah bint Abdulrahman University Researchers Supporting Project No. [PNURSP2023R3], Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia. Renyer A. Costa, Emmanoel V. Costa, Victor L. Tananta are grateful to Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) [Grant: 304577/2020-0], Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) − Code 001, and Federal University of Amazonas for financial support and fellowship.