Testing the ability of rhodanine and 2, 4-thiazolidinedione to interact with the human pancreatic alpha-amylase: electron-density descriptors complement molecular docking, QM, and QM/MM dynamics calculations

Abstract

A combined molecular docking, QM, and QM/MM dynamics modeling complemented with electron-density based descriptors computed at the B3LYP/6-311G++(d,p) level of theory have been carried out in order to understand the ability of the drugs rhodanine (RD) and 2,4-thiazolidinedione (TZD) in the effective treatment of type 2 diabetes mellitus. The global HOMO/LUMO descriptors provided just a very rough estimate of the chemical reactivity of both molecules, while the features of electron density studied in terms of its Laplacian and electrostatic potential allowed identifying the local electron rich/poor sites which were associated with the regions of electrophilic/nucleophilic attacks in RD and TZD. These results were thoroughly checked using the novel physically-grounded functional descriptors such as the phase-space Fisher information density and the internal kinetic electronic pressure density, which confirmed the information on bonding and lone electron pair details. The molecular docking, QM, and QM/MM dynamics analyses revealed the detailed picture of interactions of the drugs with the amino acid residues of the active site of the human pancreatic alpha-amylase protein (hPAA). The main difference in behavior of RD and TZD molecules is related to the hydrogen bond between the NH group of the ligand and Asp197. In hPAA complex with RD the proton from the NH group, which carries large positive charge (~ +0.45 e), spontaneously transfers to the carboxyl group of Asp197 and stays there, while in complex with TZD this proton frequently changes its position with the more preferable formation of covalent bond with the N atom. Upon deprotonation of the ligand, its hydrogen bonds with Arg195 and His299 become stronger. This process influences the binding with the difference of the binding constants of RD and TZD about 200 times with the higher value corresponding to the RD molecule. Thus, the cumulative results lead to the conclusion that rhodanine would have a higher binding affinity than the 2,4-thiazolidinedione molecule in the active site of human pancreatic alpha-amylase.

Plasmon-Induced Dimerization of Thiazolidine-2,4-dione on Silver Nanoparticles: Revealed by Surface-Enhanced Raman Scattering Study

“…The absorption spectrum of aqueous solution of TZD (Figure A­(a)) showed a band at 230 nm (5.39 eV) due to the HOMO–LUMO transition of TZD. The TD-DFT calculation also showed the HOMO–LUMO transition band at 229 nm (∼5.39 eV) and is similar to reported values . The absorption spectrum of Ag NP sol (Figure A­(b)) showed a single sharp molar extinction maximum at 395 nm due to LSP resonance.…”

“…The TD-DFT calculation also showed the HOMO−LUMO transition band at 229 nm (∼5.39 eV) and is similar to reported values. 75 The absorption spectrum of Ag NP sol (Figure 2A(b)) showed a single sharp molar extinction maximum at 395 nm due to LSP resonance. On addition of TZD to the Ag NP sol, the absorption spectrum (Figure 2A(c)) showed a second band at about 560 nm with a decrease in the absorbance of the 390 nm band.…”

Experimental Charge Density Analysis of the Anti-inflammatory Drug Meloxicam [sodium 4-hydroxy-2-methyl-N-(5-methyl-1,3-thiazol-2-yl)-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxamide Monohydrate]

“…The topological properties of covalent bonds are tabulated in Table 4 as well as in the supplementary tables. As seen in the molecules such as rhodanine and 2,4thiazolidinedione [34] the S1−O1 and S1−O2 bonds show positive Laplacian values (9.06 e /Å 5…”

Revealing electronic features governing hydrolysis of cephalosporins in the active site of the L1 metallo-β-lactamase

“…Equilibrium geometry congurations and corresponding calculated electron densities of reagents, intermediates, transition states and products of chemical reactions are analyzed by various approaches as QTAIM (Quantum Theory of Atoms in Molecules) [29][30][31][32][33][34][35][36][37][38][39][40][41] or conceptual DFT (Density Functional Theory) 23,36,[42][43][44] as well as diverse bonding descriptors. [33][34][35][36][37]45,46 Current studies of enzymatic reactions [47][48][49] also demonstrate an enhanced interest in the application of such combined methods in biochemistry. For example, the Fukui function interpreted the residue-residue interactions in biomolecular systems simulated by QM/MM method, 47 electrostatic potential allowed to identify regions of electrophilic/nucleophilic attack in the QM/MM structural models, 48,49 etc.…”

“…[33][34][35][36][37]45,46 Current studies of enzymatic reactions [47][48][49] also demonstrate an enhanced interest in the application of such combined methods in biochemistry. For example, the Fukui function interpreted the residue-residue interactions in biomolecular systems simulated by QM/MM method, 47 electrostatic potential allowed to identify regions of electrophilic/nucleophilic attack in the QM/MM structural models, 48,49 etc. Thus, here we aim to systematically examine the applicability of various available bonding descriptors in the QM/MM models of enzymatic reactions.…”