In-silico evaluation of Malawi essential medicines and reactive metabolites for potential drug-induced toxicities

Ibrahim Chikowe,Alfred Chipanda Phiri,Kirios Patrick Mbewe,Dunstan Matekenya

doi:10.1186/s40360-021-00499-6

Ibrahim Chikowe, Alfred Chipanda Phiri + Show 2 more

Open Access

https://doi.org/10.1186/s40360-021-00499-6

Copy DOI

Abstract

BackgroundDrug-induced toxicity is one of the problems that have negatively impacted on the well-being of populations throughout the world, including Malawi. It results in unnecessary hospitalizations, retarding the development of the country. This study assessed the Malawi Essential Medicines List (MEML) for structural alerts and reactive metabolites with the potential for drug-induced toxicities.MethodsThis in-silico screening study used StopTox, ToxAlerts and LD-50 values toxicity models to assess the MEML drugs. A total of 296 drugs qualified for the analysis (those that had defined chemical structures) and were screened in each software programme. Each model had its own toxicity endpoints and the models were compared for consensus of their results.ResultsIn the StopTox model, 86% of the drugs had potential to cause at least one toxicity including 55% that had the potential of causing eye irritation and corrosion. In ToxAlerts, 90% of the drugs had the potential of causing at least one toxicity and 72% were found to be potentially reactive, unstable and toxic. In LD-50, 70% of the drugs were potentially toxic.Model consensus evaluation results showed that the highest consensus was observed between ToxAlerts and StopTox (80%). The overall consensus amongst the three models was 57% and statistically significant (p < 0.05).ConclusionsA large number of drugs had the potential to cause various systemic toxicities. But the results need to be interpreted cautiously since the clinical translation of QSAR-based predictions depends on many factors. In addition, inconsistencies have been reported between screening results amongst different models.

Highlights

Drug-induced toxicity is one of the problems that have negatively impacted on the well-being of populations throughout the world, including Malawi
In the drug discovery area, all the lead compounds with structural alerts and potential to produce reactive metabolites are taken to have toxicity risk and are removed from the list or their structures are modified to get rid of the structural alerts [6,7,8]
StopTox was selected as the main software due to it being recent and easy to use as well as for its implementation of Quantitative Structure-Activity Relationships (QSAR) models developed using the best practices for validation and development required by Organisation for Economic Cooperation and Development (OECD)

Summary

Introduction

Drug-induced toxicity is one of the problems that have negatively impacted on the well-being of populations throughout the world, including Malawi. In the drug discovery area, all the lead compounds with structural alerts and potential to produce reactive metabolites are taken to have toxicity risk and are removed from the list or their structures are modified to get rid of the structural alerts [6,7,8] This may bring challenges if the structural alerts are part of the pharmacophore (the functional group responsible for drug candidate activity) as it is for structural alerts such as furan, thiophene, nitroaromatic, phenol, and aniline that are known to be pharmacophores [9]. They can give rise to a pharmacological activity or provide pharmacokinetic benefits

Methods

Results

Discussion

Conclusion