Quantitative Structure–Toxicity Relationship in Bioactive Molecules from a Conceptual DFT Perspective

Abstract

The preclinical drug discovery stage often requires a large amount of costly and time-consuming experiments using huge sets of chemical compounds. In the last few decades, this process has undergone significant improvements by the introduction of quantitative structure-activity relationship (QSAR) modelling that uses a certain percentage of experimental data to predict the biological activity/property of compounds with similar structural skeleton and/or containing a particular functional group(s). The use of machine learning tools along with it has made life even easier for pharmaceutical researchers. Here, we discuss the toxicity of certain sets of bioactive compounds towards Pimephales promelas and Tetrahymena pyriformis in terms of the global conceptual density functional theory (CDFT)-based descriptor, electrophilicity index (ω). We have compared the results with those obtained by using the commonly used hydrophobicity parameter, logP (where P is the n-octanol/water partition coefficient), considering the greater ease of computing the ω descriptor. The Human African trypanosomiasis (HAT) curing activity of 32 pyridyl benzamide derivatives is also studied against Tryphanosoma brucei. In this review article, we summarize these multiple linear regression (MLR)-based QSAR studies in terms of electrophilicity (ω, ω2) and hydrophobicity (logP, (logP)2) parameters.

Design of β-Keto Esters with Antibacterial Activity: Synthesis, In Vitro Evaluation, and Theoretical Assessment of Their Reactivity and Quorum-Sensing Inhibition Capacity

“…Lipophilicity (hydrophobicity) has been the main focus in this area. However, electronic characteristics related to electrophile-nucleophile reactivity have also emerged as effective parameters to preliminarily assess the biological and toxicological activities of compounds of pharmacological interest [25][26][27].…”

“…The description of the electronic aspect of the compounds is critical, for example, in aqueous toxicity mechanisms where nucleophile-electrophile interactions are the driving force [27]. It has been described that strong electrophiles can exert toxicity by covalently bonding with biological nucleophiles such as the cysteine or lysine amino-acid residues in enzymes, among others [37].…”

“…In order to analyse the local reactivity of the β-keto esters at more reactive positions, C-carbonyl atoms 1 and 3, we calculated the condensed Fukui functions for an To study the susceptibility of β-keto esters 1-8 to suffering a reaction with biological nucleophiles, we employed reactivity descriptors from conceptual DFT [27,38,39], which are presented in Table 3. The results for the electronic chemical potential (µ) show that compound 3 presented the highest escaping tendency of its electrons from equilibrium, while compound 7 presents the lowest tendency.…”