Combined experimental and computational investigation of vildagliptin: spectroscopy, electronic structure, MD and Docking to EGFR, VEGFR2, and HER2 anticancer targets

Abstract

This study combines experimental and computational approaches to investigate the molecular geometry and physicochemical properties of vildagliptin (VILD). Using methods such as UV-Vis, spectrofluorimetry, FTIR/Raman, and circular dichroism alongside DFT, molecular docking, and dynamics simulations, a reliable molecular model was obtained that aligns closely with X-ray crystallographic data. This model enabled accurate predictions of vibrational frequencies and systematic assignments of vibrational modes. Analyses, including Hirshfeld surface mapping, molecular electrostatic potential, HOMO-LUMO energetics, Fukui indices, and natural population analysis, provided clear insights into VILD's reactivity, while NBO and TD-DFT studies elucidated key stabilizing interactions and high-energy electronic transitions. NTO visualization further clarified orbital dynamics, and circular dichroism measurements explained the molecular basis of the Cotton effect. Additionally, molecular docking and molecular dynamics simulations confirmed the formation of stable complexes with EGFR, VEGFR2, and HER2 receptor proteins, suggesting potential anticancer activity. The main purpose of this publication is to fill existing gaps in our understanding of VILD's molecular behavior and offer a robust foundation for rational drug design and improved therapeutic strategies.

Keywords: DFT; FTIR; Raman; Spectroscopy; Vildagliptin.

Fig. 1

Optimized structure of vildagliptin and atom numbering

Fig. 2

Experimental A and theoretical, B FTIR spectra of vildagliptin

Fig. 3

Experimental A and theoretical, B Raman spectra of vildagliptin

Fig. 4

Hirshfeld surface of VILD mapped over d_norm

Fig. 5

2D finger plot graphs representing the number of molecular interactions of VILD. A– O H interactions, B– H–H interactions, C– N–H interactions, D– C–H interactions

Fig. 6

Molecular electrostatic potential surface (MEP) of vildagliptin

Fig. 7

Frontier molecular orbitals of VILD calculated with DFT

Fig. 8

Experimental and theoretical UV-Vis spectra of vildagliptin solution in methanol

Fig. 9

Representation of natural transition orbitals (NTO) of the “particle” and “hole” pairs for the VILD excitations

Fig. 10

Density of state spectrum of VILD

Fig. 11

Experimental and theoretical circular dichroism spectra of VILD

Fig. 12

3D fluorimetric spectrum of vildagliptin solution in methanol

Fig. 13

Entropy, enthalpy and heat capacity curves calculated for vildagliptin

Fig. 14

Docking results of VILD and three analyzed proteins with specified, nearest amino acids interacting with the ligand

Fig. 15

RMSD, RMSF curves, radius of gyration and a number of hydrogen bonds formed between VILD and three analyzed proteins

Fig. 16

The occupancy plot of the amino acid residues of proteins in contact with VILD (the number of simulation frames from the last 50 ns of MD production run)

Fig. 17

Binding energies with energy components of VILD complexes with 1M17, 4AG8 and 3PP0 proteins