Structural analysis and computational studies of cyclopropane derivative as an anti- Alzheimer’s agent: Investigation of interactions by X-ray crystallography, DFT, molecular docking, and ADMET approaches

Rajesh, S. M. and Vinay Kumar, D. C. and Shalini, V. and Harsha, K. B. and Darshini, G. and Rangappa, K. S. (2025) Structural analysis and computational studies of cyclopropane derivative as an anti- Alzheimer’s agent: Investigation of interactions by X-ray crystallography, DFT, molecular docking, and ADMET approaches. Journal of Molecular Structure, 1341. ISSN 0022-2860

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Abstract

A novel 2-benzoyl-1"-methyl-3-phenylspiro(cyclopropane-1",3-indolin)-2"-one compound (Spiro compound) was synthesized with good yield of 88% via cyclization reaction using sulphur yields. Their efficacy against sodium-dependent serotonin transporter (SERT or 5-HTT) protein that controls mood, impulsivity, and violence depend on serotonin was evaluated using in silico methods. Spectroscopic methods such as LCMS, NMR, and FTIR were used to characterize the structures of the synthesized Spiro molecule. The ab-initio analyses were carried out encompassing quantum chemical computations, molecular docking, and ADMET profiling. The single crystal Xray structure of the Spiro compound was successfully obtained, according to which the Spiro compound crystallizes in the monoclinic crystal system with P21/c space group. Further the crystal structure exhibited intra and inter molecular interactions forming various types of self-motifs and supra molecular synthons. These interactions were further visualized and quantified using Hirshfeld surface analysis and 2D finger print plots. The Spiro compound structure was optimized using density functional theory calculations at B3LYP/6-311++g(d,p) level basis set, which showed a very good correlation between the DFT and XRD structures with an RMSD value of 0.465 & Aring;. In addition, the synthesized compound's HOMO (pi donor) and LUMO (pi acceptor), MEP surface, electronic properties, quantum chemical reactivity showed a promising reactivity profile, according to DFT studies. Both local and global reactivity descriptors, such as chemical potential, electronegativity, hardness, softness, and electrophilicity index, determined using the DFT. This difference emphasizes how various molecular constituents work in tandem to promote chemical reaction. Further, the docking analysis between SERT protein and Spiro compound showed docking score of-8.5 kcal/mol, indicating favourable binding affinity. The docking results were compared with that of the standard medication drug, Rivastigmine, with the binding score of-6.2 kcal/mol, indicating the Spiro compound as could be a lead anti-Alzimeric drug. According to Lipinski's, Ghose, Veber, and Egan rules, the Spiro compound falls within acceptable safety profiles. Here, we explain how in silico methods will speed up the drug development process by improving our capacity to forecast and model the most pertinent pharmacokinetic, metabolic, and toxicological endpoints.

Item Type:	Article
Uncontrolled Keywords:	Spiro compound, Single crystal, DFT, SERT, Docking, ADMET
Subjects:	C Chemical Science > Chemistry
Divisions:	Department of > Chemistry
Depositing User:	Ms Varalakshmi
Date Deposited:	30 Oct 2025 05:49
Last Modified:	30 Oct 2025 10:01
URI:	http://eprints.uni-mysore.ac.in/id/eprint/17883

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