New In Silico Insights into the Application of (Hydroxy)Chloroquine with Macrolide Antibiotic Co-Crystals against the SARS-CoV-2 Virus

Alexandre A De Castro,Teodorico C Ramalho,Letícia C Assis,Elaine F F Da Cunha,Felipe A La Porta

doi:10.3390/covid2030018

Abstract

In this in silico study, different pharmaceutical co-crystals based on (hydroxy)chloroquine with macrolide antibiotics (azithromycin, clarithromycin, or erythromycin A) were analyzed for the first time. These findings present a new molecular perspective and therefore suggest that the combination of (hydroxy)chloroquine/azithromycin, in the stoichiometric ratio of 1:1, as model co-crystal systems has less toxicity and is the most effective for inhibiting the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Highlights

AZ and CL are well-known semi-synthetic derivatives of ER, the first and most-known macrolide antibiotic to be isolated in 1952 [20–22]. These macrolide antibiotics are mainly used to treat patients with certain infections of the respiratory tract [20]. It is well-known that the combination of AZ with antimalarial drugs (e.g.,chloroquine), shows some crucial benefits for the treatment of malaria [23]
A third relevant aspect of this study is that bothchloroquine and macrolide antibiotics usually crystallize in a monoclinic structure according to the CSD
Interpretation our theoreticaloffindings are of great importance and provide a new level, andperspective in this direction, strategies and can toxicity contribute to accelerating the process molecular on thesuch effectiveness of co-crystals formed betweenof developing new drugs

Summary

Computational Details

The unit cell of these compounds was replicated for the investigated set of single and co-crystals, that is, their structural parameters were maintained as similar as possible All of these model systems were optimized (as the starting point for docking studies), and their structural and vibrational properties were fully evaluated at the PM6 theoretical level, using the Gaussian 09 package [31]. Taking into account the experimental inexistence of acute toxicity data for the compounds employed in this study and in order to estimate the theoretical values of the lethal dose (denoted as LD50 ), a rat model-based admetSAR predictor was used This admetSAR approach is freely available online at http://lmmd.ecust.edu.cn:8000/ (accessed on 15 August 2020).

Results and Discussion

Note that the single crystals

Conclusions