Virtual Screening Based on QSAR and Molecular Docking of Possible Inhibitors Targeting Chagas CYP51

S Cotes,J Cotuá,H Llinás,Ester Chiessi

doi:10.1155/2021/6640624

S Cotes, J Cotuá + Show 2 more

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https://doi.org/10.1155/2021/6640624

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Abstract

Chagas is a neglected tropical disease caused by the parasite Trypanosoma cruzi with no effective treatment in all its forms. There is a need to find more effective therapeutic alternatives with reduced toxicity. In this contribution, multiple linear regression models were used to identify the molecular descriptors that best describe the inhibitory activity of 52 fenarimol analogues against Trypanosoma cruzi. The topological, physicochemical, thermodynamic, electronic, and charge descriptors were evaluated to cover a wide range of properties that frequently encode biological activity. A model with high predictive value was obtained based on geometrical descriptors and descriptors encoding hydrophobicity and London dispersion forces as necessary for the inhibition of Trypanosoma cruzi-CYP51. Docking methodology was implemented to evaluate molecular interactions in silico. The virtual screening results in this study can be used for rational design of new analogues with improved activity against Chagas disease.

Highlights

A tropical disease endemic to Latin America, is caused by the parasite Trypanosoma cruzi (T. cruzi), first described in 1909 [1,2,3]. e most affected population is very low-income people, who do not have the economic resources to pay for expensive treatments and live in conditions of high vulnerability [4,5,6]. e pharmacological therapy currently used is aimed at preventing the chronicity of the infection since the efficacy of antiparasitic drugs decreases in the chronic phases of the disease. e effectiveness of the treatment in the acute phase has been demonstrated [7], while the chronic stage can take up to 20 years resulting in multiple-organ damage [6,7,8]
Pharmacological data of 52 fenarimol analogues were taken from the literature [35]. pIC50 (−logIC50) was used as a measure of biological activity, IC50 values corresponding to concentration of the compound required to inhibit 50% of T. cruzi measured under the same experimental conditions
Twelve descriptors were identified and statistically validated to build a Quantitative structure-activity relationship (QSAR) model. e length, Q-VSA_FPPOS, and Log P(o/w) are determinant descriptors in the prediction of biological activity against Chagas disease. e multiple linear regression (MLR) model has demonstrated that the most active compounds have low values of Q-VSA_FPPOS and high values of length and Log P(o/w). e stability and robustness of the model are supported by the statistical parameters and validation tests applied, indicating that the strategy implemented in this study can be used to predict the biological activity of piperazine analogues of fenarimol and to adopt a rational design for developing new analogues with improved activity against Chagas disease

Summary

Introduction

A tropical disease endemic to Latin America, is caused by the parasite Trypanosoma cruzi (T. cruzi), first described in 1909 [1,2,3]. e most affected population is very low-income people, who do not have the economic resources to pay for expensive treatments and live in conditions of high vulnerability [4,5,6]. e pharmacological therapy currently used is aimed at preventing the chronicity of the infection since the efficacy of antiparasitic drugs decreases in the chronic phases of the disease. e effectiveness of the treatment in the acute phase has been demonstrated [7], while the chronic stage can take up to 20 years resulting in multiple-organ damage [6,7,8]. Ere is no effective treatment for Chagas disease in all its forms; treatment with nifurtimox and benznidazole is highly toxic [6, 7, 11]. Both compounds are heterocyclic with a furan and imidazole-nitrogenated ring, respectively, which act by inducing cytotoxicity in the parasite by interacting with the nitroreductase enzymes of the parasites [12,13,14,15]. Benznidazole and nifurtimox contain nitro groups that produce nitrogenated metabolic radicals that affect the parasite and are responsible for the toxicity, mutagenicity, genotoxicity, and carcinogenicity attributed to them [17]. Sterol 14α-demethylase cytochrome P450 (CYP51) inhibitors with trypanocidal activity have been identified

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