Chemoinformatics Studies on a Series of Imidazoles as Cruzain Inhibitors.

Alex R Medeiros,Mariana L De Souza,Celso De Oliveira Rezende Junior,Leonardo L G Ferreira,Luiz Carlos Dias,Adriano D Andricopulo,Rocío Marisol Espinoza-Chávez

doi:10.3390/biom11040579

Alex R Medeiros, Mariana L De Souza + Show 5 more

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https://doi.org/10.3390/biom11040579

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Abstract

Natural products based on imidazole scaffolds have inspired the discovery of a wide variety of bioactive compounds. Herein, a series of imidazoles that act as competitive and potent cruzain inhibitors was investigated using a combination of ligand- and structure-based drug design strategies. Quantitative structure–activity relationships (QSARs) were generated along with the investigation of enzyme–inhibitor molecular interactions. Predictive hologram QSAR (HQSAR, r2pred = 0.80) and AutoQSAR (q2 = 0.90) models were built, and key structural properties that underpin cruzain inhibition were identified. Moreover, comparative molecular field analysis (CoMFA, r2pred = 0.81) and comparative molecular similarity indices analysis (CoMSIA, r2pred = 0.73) revealed 3D molecular features that strongly affect the activity of the inhibitors. These findings were examined along with molecular docking studies and were highly compatible with the intermolecular contacts that take place between cruzain and the inhibitors. The results gathered herein revealed the main factors that determine the activity of the imidazoles studied and provide novel knowledge for the design of improved cruzain inhibitors.

Highlights

The hologram QSAR (HQSAR), AutoQSAR, comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA) models were built as previously described [21,22,23,24] using SYBYL-X 2.1 (Certara Inc., Princeton, NJ, USA) and Maestro
The dataset used to build the Quantitative structure–activity relationships (QSARs) models consists of 37 compounds (Table 1) that were designed and tested against cruzain in our research group
The series was designed based on the structure of lead compound 1, which is a competitive cruzain inhibitor identified in a virtual screening effort [13]

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Neglected tropical diseases (NTDs) affect more than 1.5 billion people worldwide in more than 150 countries, mainly in developing nations [1]. Among NTDs, Chagas disease is endemic in 21 Latin American countries and affects 6 to 7 million people worldwide [2]. The highest burden in a nonendemic country occurs in the USA, where approximately

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