Virtual Screening of Marine Natural Compounds by Means of Chemoinformatics and CDFT-Based Computational Peptidology.

Norma Flores-Holguín,Daniel Glossman-Mitnik,Juan Frau

doi:10.3390/md18090478

Abstract

This work presents the results of a computational study of the chemical reactivity and bioactivity properties of the members of the theopapuamides A-D family of marine peptides by making use of our proposed methodology named Computational Peptidology (CP) that has been successfully considered in previous studies of this kind of molecular system. CP allows for the determination of the global and local descriptors that come from Conceptual Density Functional Theory (CDFT) that can give an idea about the chemical reactivity properties of the marine natural products under study, which are expected to be related to their bioactivity. At the same time, the validity of the procedure based on the adoption of the KID (Koopmans In DFT) technique, as well as the MN12SX/Def2TZVP/H2O model chemistry is successfully verified. Together with several chemoinformatic tools that can be used to improve the process of virtual screening, some additional properties of these marine peptides are identified related to their ability to behave as useful drugs. With the further objective of analyzing their bioactivity, some useful parameters for future QSAR studies, their predicted biological targets, and the ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) parameters related to the theopapuamides A-D pharmacokinetics are also reported.

Highlights

Drug design can be pursued following a methodology driven by advancement and innovation breakthroughs including a combination of experimental and computational strategies.Computational strategies play a pivotal part in advanced therapeutic chemistry, displaying a special potential for changing the early stages in the process of drug discovery, especially in terms of time and cost savings [1,2].Bioactive peptides are short amino acid chains that are inactive within the sequence of the parent protein and can be activated through gastrointestinal digestion, food processing, storage, or in vitro hydrolysis by proteolytic enzymes
The theopapuamides A-D family of cyclodepsipeptides of marine origin are studied by resorting to some techniques of common use in the process of drug discovery and development, showing that these kinds of molecules can be regarded as potential therapeutic drugs
Some chemoinformatic tools are used to obtain information about the potential therapeutic properties of these peptides in the form of bioactivity radar charts, biological targets, and ADME values. With this knowledge in mind, the chemical reactivity of the studied peptides is exhaustively analyzed through the optimization of their structures using an MN12SX/Def2SVP/H2O model chemistry and the determination of their electronic properties by means of a larger model chemistry, namely MN12SX/Def2TZVP/H2O, already used in previous works for the study of peptides, validating their usefulness for these kinds of calculations

Summary

Introduction

Computational strategies play a pivotal part in advanced therapeutic chemistry, displaying a special potential for changing the early stages in the process of drug discovery, especially in terms of time and cost savings [1,2]. Bioactive peptides are short amino acid chains that are inactive within the sequence of the parent protein and can be activated through gastrointestinal digestion, food processing, storage, or in vitro hydrolysis by proteolytic enzymes. Computational chemistry and molecular modeling tools provide methodologies to identify peptide sequences and their 3D molecular structure. These molecular structures can be related to biological activity and targets of interest.

Objectives

Results

Conclusion