Computational Peptidology Assisted by Conceptual Density Functional Theory for the Study of Five New Antifungal Tripeptides

Abstract

A well-behaved model chemistry previously validated for the study of the chemical reactivity of peptides was considered for the calculation of the molecular properties and structures of a group of five new antifungal tripeptides, namely (2 R )-2-[(2 S )-2-[(2 S )-2-amino-3-phenylpropanamido]propanamido]-5-[(diaminomethylidene)amino]pentanoic acid, (2 S )-2-[(2 S )-2-[(2 S )-2-amino-3-phenyl propanamido]propanamido]-3-(4-hydroxyphenyl)propanoic acid, (2 S )-2-[(2 S )-2-[(2 S )-2-amino-3-phenylpropanamido]-3-methylbutanamido]-3-(4-hydroxyphenyl)propanoic acid, (2 R )-2-[(2 S )-2-[(2 S )-2-amino-3-phenylpropanamido]-3-(1 H -indol-3-yl)propanamido]-3-sulfanylpropanoic acid, and (2 S )-2-[(2 S )-2-[(2 S )-2-amino-3-phenylpropanamido]-3-(1 H -indol-3-yl)propanamido]-3-(4-hydroxyphenyl)propanoic acid, according to their amino acid sequences. A methodology based on conceptual density functional theory was chosen for the determination of the reactivity descriptors. The molecular active sites were associated with the active regions of the molecules that were associated with the nucleophilic, electrophilic, and radical Fukui functions. Additionally, the p K a values for the different peptides are predicted with great accuracy, which constitutes a useful knowledge for the process of drug design. Finally, the bioactivity scores for the new antifungal peptides are predicted through a homology methodology relating them with the calculated reactivity descriptors.

Calculation of the Global and Local Conceptual DFT Indices for the Prediction of the Chemical Reactivity Properties of Papuamides A–F Marine Drugs

“…As a follow up of previous research on the subject [41,42,43,44,45], this study sought to assess the chemical reactivity properties of the Papuamides family of marine peptides through the application of the Density Functional Theory concepts as well as the determination of their drug-likeness, bioactivity scores and pharmacokinetics based on the online Molinspiration program and on SwissADME, a free web tool for the evaluation of those properties [30,31,32,46,47,48].…”

“…In the process of calculating the electronic properties for the chemical reactivity of the antimicrobial peptides involved the use of MN12SX/Def2TZVP/H2O model chemistry through the optimized molecular structures, as explained in detail in Section 3. The choice of this model chemistry was based in the fact that, according to our previous research [41,42,43,44,45], it allows obtaining HOMO (Highest Occupied Molecular Orbital) and LUMO (Lowest Unoccupied Molecular Orbital) energies that verify the KID procedure (Koopmans in DFT) making easier the determination of the chemical reactivity descriptors arising from Conceptual DFT.…”

Conceptual DFT as a Novel Chemoinformatics Tool for Studying the Chemical Reactivity Properties of the Amatoxin Family of Fungal Peptides

“…The resulting lowest energy conformers for each peptide obtained during this process were then reoptimized through the Density Functional Tight Binding (DFTBA) functionality accesible within the Gaussian 09 software [22]. By considering the experience acquired in the previous research of our group [11,[23][24][25][26][27][28][29][30], the model chemistry based on the association of the MN12SX functional with the Def2TZVP basis set using water as the solvent was con-sidered for the final optimization of the resulting molecular structures because it has been shown that it allows the verification of the 'Koopmans in DFT' (KID) procedure [11,[23][24][25][26][27][28][29][30]. In the same way, the process for the calculation of the electronic properties and the chemical reactivity descriptors of the fungal peptides involved the use of MN12SX/Def2TZVP/H2O model chemistry through the consideration of the previously optimized molecular structures.…”

“…It has been shown by Frau and Glossman-Mitnik [11,[23][24][25][26][27][28][29][30] that the HOMO (Highest Occupied Molecular Orbital) and LUMO (Lowest Unoccupied Molecular Orbital) energies obtained with the MN12SX/Def2TZVP/H2O model chemistry allows the verification of the KID procedure, that is, rendering an approximate Koopmans behavior. With the aid of the KID technique and the finite difference approximation [11,[23][24][25][26][27][28][29][30], the following expressions can be used to define the global reactivity descriptors [14-16, 35, 36]: Electronegativity…”

“…This research seeks to obtain the chemical reactivity information of the fungal peptides under study by means of the consideration of the Density Functional Theory (DFT) derived concepts. There is a lot of research where the Conceptual DFT is used to relate the reactivity of several compounds with biological activity [5][6][7][8][9][10][11]. The understanding of the chemical reactivity properties of the Amatoxin molecules will be crucially achieved by means of the consideration of the Fukui functions to extract the information about the reactivity of the peptides which can be of potential utility in the process of designin new pharmaceutical drugs [12][13][14][15][16].…”