Structure-based virtual screening of mangiferin derivatives with antidiabetic action: a molecular docking and dynamics study and MPO-based drug-likeness approach

Abstract

Extracts from Mangifera indica leaves and its main component, mangiferin, have proven antidiabetic activity. In this study, mangiferin and its natural derivatives Homomangiferin (HMF), Isomangiferin (IMF), Neomangiferin (NMF), Glucomangiferin (GMF), Mangiferin 6'-gallate (MFG), and Norathyriol (NRT) were compared regarding their action on Diabetes mellitus (DM), employing docking and molecular dynamics (MD) simulations to analyze interactions with the aldose reductase enzyme, the precursor to the conversion of glucose into sorbitol. Notably, HMF showed significant affinity to residues in the active site of the enzyme, including Trp 79, His 110, Trp 111, Phe 122, and Phe 300, with an energy of - 7.2 kcal/mol, observed in the molecular docking simulations. MD reinforced the formation of stable complexes for HMF and MFG with the aldose reductase, with interaction potential energies (IPE) in the order of - 300.812 ± 52 kJ/mol and - 304.812 ± 52 kJ/mol, respectively. The drug-likeness assessment, by multiparameter optimization (MPO), highlighted that HMF and IMF have similarities with polyphenols and glycosidic flavonoids recently patented as antidiabetics, revealing that high polarity (TPSA > 180 Ų) is a favorable property for subcutaneous administration, especially because of the gradual passive cell permeability values in biological tissues, with P_app values estimated at < 10 × 10^-6 cm/s. These compounds are metabolically stable against metabolic enzymes, resulting in a low toxic incidence by metabolic activation, corroborating with a lethal dose (LD₅₀) greater than 2000 mg/kg. In this way, HMF showed a systematic alignment between predicted pharmacokinetics and pharmacodynamics, characterizing it as the most favorable substance for inhibiting aldose reductase.

Supplementary information: The online version contains supplementary material available at 10.1007/s13205-024-03978-9.

Keywords: Antidiabetic; Drug-likeness; Dynamics; Mangiferin derivatives; Molecular docking.

Fig. 1

Two-dimensional representation of the chemical structures of Norathyriol (NRT), Homomangiferin (HMF), Mangiferin (MF), Isomangiferin (IMF), Neomangiferin (NMF), Glucomangiferin (GMF), and Mangiferin 6’-gallate (MFG)

Fig. 2

Virtual screening of A target classes and B 3D/2D similarity prediction against aldose reductase

Fig. 3

A interaction of the LIT inhibitor with the residues present in the active site; B Docking positions of the LIT inhibitor at the Aldose Reductase Human; C distance between the ligand-receptor represented by a spectrum with the residues interacting with the residues of Human Aldose Reductase

Fig. 4

A interactions carried out by the derivative ligands NRT, HML, and IML against the enzyme; B Heatmap of the distances of interactions between residues and ligands; C Affinity energy values of ligands NRT, HML, and IML

Fig. 5

A Interactions between the amino acids of the protein and the ligands MF, GMF, NMF, and MFG; B region of interest between the ligands and the protein cavity; C heat map of interactions with residues of interest that interact with the cited ligands; D binding energy values in kcal/mol

Fig. 6

A RMSD results of the LIT compound, theoretical protein inhibitor, B RMSD of the NRT compound, C RMSD values with the HMF ligand, D RMSD in triplicates of the system formed with the IMF compound, E RMSD with the MF ligand, F RMSD result in complex with the NMF ligand, G RMSD of the GMF ligand, and H RMSD values with the MFG compound

Fig. 7

A fluctuation of amino acid residues with the ligands LIT (black), NRT (red), HML (green), and IMF (blue); B fluctuation of the other ligands MF (black), GMF (red), NMF (green), and MFG (blue)

Fig. 8

H-Bond occupancy values of the LIT inhibitor, in relation to the protein residues: Don = donor; ACC = acceptor

Fig. 9

H-Bond occupancy values of NMF (A), GMF (B), and MFG (C) ligands; in front of protein residues. Don donor, ACC acceptor

Fig. 10

Spectrum of the relationship between Fsp3 and structural complexity in estimating the gau of similarity of NRT glycosylated analogs to patent-pending substances according to MCE-18 trends

Fig. 11

Alignment between logP and TPSA for drug-space estimation related to human intestinal absorption (HIA) and CNS distribution of NRT and its glycoside analogs

Fig. 12

Prediction of LD₅₀ (in mg/kg) for glycosylated NRT analogs for different administration routes: oral, intravenous (IV), and subcutaneous (SC)