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Prediction Model for Antimalarial Activities of Hemozoin Inhibitors by Using Physicochemical Properties.

ABSTRACT: The rapid spread of strains of malaria parasites that are resistant to several drugs has threatened global malaria control. Hence, the aim of this study was to predict the antimalarial activity of chemical compounds that possess anti-hemozoin-formation activity as a new means of antimalarial drug discovery. After the initial in vitro anti-hemozoin-formation high-throughput screening (HTS) of 9,600 compounds, a total of 224 hit compounds were identified as hemozoin inhibitors. These 224 compounds were tested for in vitro erythrocytic antimalarial activity at 10 ?M by using chloroquine-mefloquine-sensitive Plasmodium falciparum strain 3D7A. Two independent experiments were conducted. The physicochemical properties of the active compounds were extracted from the ChemSpider and SciFinder databases. We analyzed the extracted data by using Bayesian model averaging (BMA). Our findings revealed that lower numbers of S atoms; lower distribution coefficient (log D) values at pH 3, 4, and 5; and higher predicted distribution coefficient (ACD log D) values at pH 7.4 had significant associations with antimalarial activity among compounds that possess anti-hemozoin-formation activity. The BMA model revealed an accuracy of 91.23%. We report new prediction models containing physicochemical properties that shed light on effective chemical groups for synthetic antimalarial compounds and help with in silico screening for novel antimalarial drugs.

SUBMITTER: Mosaddeque F

PROVIDER: S-EPMC5923155 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Prediction Model for Antimalarial Activities of Hemozoin Inhibitors by Using Physicochemical Properties.

Mosaddeque Farhana F Mizukami Shusaku S Kamel Mohamed Gomaa MG Teklemichael Awet Alem AA Dat Truong Van TV Mizuta Satoshi S Toan Dinh Van DV Ahmed Ali Mahmoud AM Vuong Nguyen Lam NL Elhady Mohamed Tamer MT Giang Hoang Thi Nam HTN Dang Tran Ngoc TN Fukuda Michiko M Huynh Lam K LK Tanaka Yoshimasa Y Egan Timothy J TJ Kaneko Osamu O Huy Nguyen Tien NT Hirayama Kenji K

Antimicrobial agents and chemotherapy 20180426 5

The rapid spread of strains of malaria parasites that are resistant to several drugs has threatened global malaria control. Hence, the aim of this study was to predict the antimalarial activity of chemical compounds that possess anti-hemozoin-formation activity as a new means of antimalarial drug discovery. After the initial <i>in vitro</i> anti-hemozoin-formation high-throughput screening (HTS) of 9,600 compounds, a total of 224 hit compounds were identified as hemozoin inhibitors. These 224 co ...[more]

PMID: 29439979

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Project description:BACKGROUND: Hemozoin crystals are normally formed in vivo by Plasmodium parasites to detoxify free heme released after hemoglobin digestion during its intraerythrocytic stage. Inhibition of hemozoin formation by various drugs results in free heme concentration toxic for the parasites. As a consequence, in vitro assays have been developed to screen and select candidate antimalarial drugs based on their capacity to inhibit hemozoin formation. In this report we describe new ways to form hemozoin-like crystals that were incidentally discovered during research in the field of prion inactivation. METHODS: We investigated the use of a new assay based on naturally occurring "self-replicating" particles and previously described as presenting resistance to decontamination comparable to prions. The nature of these particles was determined using electron microscopy, Maldi-Tof analysis and X-ray diffraction. They were compared to synthetic hemozoin and to hemozoin obtained from Plasmodium falciparum. We then used the assay to evaluate the capacity of various antimalarial and anti-prion compounds to inhibit "self-replication" (crystallisation) of these particles. RESULTS: We identified these particles as being similar to ferriprotoporphyrin IX crystal and confirmed the ability of these particles to serve as nuclei for growth of new hemozoin-like crystals (HLC). HLC are morphologically similar to natural and synthetic hemozoin. Growth of HLC in a simple assay format confirmed inhibition by quinolines antimalarials at potencies described in the literature. Interestingly, artemisinins and tetracyclines also seemed to inhibit HLC growth. CONCLUSIONS: The described HLC assay is simple and easy to perform and may have the potential to be used as an additional tool to screen antimalarial drugs for their hemozoin inhibiting activity. As already described by others, drugs that inhibit hemozoin crystal formation have also the potential to inhibit misfolded proteins assemblies formation.

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Prediction Model for Antimalarial Activities of Hemozoin Inhibitors by Using Physicochemical Properties.

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Prediction Model for Antimalarial Activities of Hemozoin Inhibitors by Using Physicochemical Properties.

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