In silico analysis for factors affecting anti-malarial penetration into red blood cells

Natapol Pornputtapong,Anchisa Satayamapakorn,Phisit Khemawoot,Pariyachut Janviriyakul,Bovornpat Suriyapakorn,Kanidsorn Larpadisorn

doi:10.1186/s12936-020-03280-y

In silico analysis for factors affecting anti-malarial penetration into red blood cells

Natapol Pornputtapong, Anchisa Satayamapakorn + Show 4 more

Open Access

https://doi.org/10.1186/s12936-020-03280-y

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Abstract

BackgroundMalaria is a parasitic disease that produces significant infection in red blood cells. The objective of this study is to investigate the relationships between factors affecting the penetration of currently available anti-malarials into red blood cells.MethodsFifteen anti-malarial drugs listed in the third edition of the World Health Organization malaria treatment guidelines were enrolled in the study. Relationship analysis began with the prioritization of the physicochemical properties of the anti-malarials to create a multivariate linear regression model that correlates the red blood cell penetration.ResultsIt was found that protein binding was significantly correlated with red blood cell penetration, with a negative coefficient. The next step was repeated analysis to find molecular descriptors that influence protein binding. The coefficients of the number of rotating bonds and the number of aliphatic hydrocarbons are negative, as opposed to the positive coefficients of the number of hydrogen bonds and the number of aromatic hydrocarbons. The p-value was less than 0.05.ConclusionsAnti-malarials with a small number of hydrogen bonds and aromatic hydrocarbons, together with a high number of rotatable bonds and aliphatic hydrocarbons, may have a higher tendency to penetrate the red blood cells.

Highlights

Malaria is a parasitic disease that produces significant infection in red blood cells
Study on the relationships between factors influencing the red blood cell penetration of anti‐malarial drugs From the important factors analysis, protein binding, logP, water solubility, and molecular weight were considered as the most important factors and used as a feature set for extreme gradient boosting model construction
Study of the relationships between the molecular descriptors affecting protein binding From the important factors analysis, the number of rotatable bonds was the most important, followed by the number of hydrogen bond acceptors

Summary

Introduction

Malaria is a parasitic disease that produces significant infection in red blood cells. The objective of this study is to investigate the relationships between factors affecting the penetration of currently available anti-malarials into red blood cells. Malaria is an infectious disease generated by Plasmodium spp., which continues to be a public health problem in Thailand. The 2018 Thai guidelines for the treatment of malaria recommend artemisinin-based combination therapy as the first-line regimen [1]. The firstgeneration artemisinin derivatives, including artemisinin, artemether, arteether, artesunate, and dihydroartemisinin, are still widely used [2]. Each derivative penetrates the red Pornputtapong et al Malar J (2020) 19:215 Drug. Amodiaquine Arteether Artemether Artemisinin Artesunate Chloroquine Dihydroartemisinin Doxycycline Mefloquine Piperaquine Primaquine Proguanil Pyrimethamine Quinine Sulfadoxine. 1.313 [7] 0.23 [10] 0.28 [10] 0.49 [10] 0.71 [10] 4.8 [16] 0.52 [10] 0.37 [19] 2.8 [21] 1.5 [22] 1 [25] 4.9 [27] 0.42 [28] 1.89 [30] 0.163 [31] LogP [8]

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