Dataset Information

Lapatinib, Nilotinib and Lomitapide Inhibit Haemozoin Formation in Malaria Parasites.

ABSTRACT: With the continued loss of antimalarials to resistance, drug repositioning may have a role in maximising efficiency and accelerating the discovery of new antimalarial drugs. Bayesian statistics was previously used as a tool to virtually screen USFDA approved drugs for predicted ?-haematin (synthetic haemozoin) inhibition and in vitro antimalarial activity. Here, we report the experimental evaluation of nine of the highest ranked drugs, confirming the accuracy of the model by showing an overall 93% hit rate. Lapatinib, nilotinib, and lomitapide showed the best activity for inhibition of ?-haematin formation and parasite growth and were found to inhibit haemozoin formation in the parasite, providing mechanistic insights into their mode of antimalarial action. We then screened the USFDA approved drugs for binding to the ?-haematin crystal, applying a docking method in order to evaluate its performance. The docking method correctly identified imatinib, lapatinib, nilotinib, and lomitapide. Experimental evaluation of 22 of the highest ranked purchasable drugs showed a 24% hit rate. Lapatinib and nilotinib were chosen as templates for shape and electrostatic similarity screening for lead hopping using the in-stock ChemDiv compound catalogue. The actives were novel structures worthy of future investigation. This study presents a comparison of different in silico methods to identify new haemozoin-inhibiting chemotherapeutic alternatives for malaria that proved to be useful in different ways when taking into consideration their strengths and limitations.

SUBMITTER: de Sousa ACC

PROVIDER: S-EPMC7180468 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Lapatinib, Nilotinib and Lomitapide Inhibit Haemozoin Formation in Malaria Parasites.

de Sousa Ana Carolina C ACC Maepa Keletso K Combrinck Jill M JM Egan Timothy J TJ

Molecules (Basel, Switzerland) 20200329 7

With the continued loss of antimalarials to resistance, drug repositioning may have a role in maximising efficiency and accelerating the discovery of new antimalarial drugs. Bayesian statistics was previously used as a tool to virtually screen USFDA approved drugs for predicted β-haematin (synthetic haemozoin) inhibition and in vitro antimalarial activity. Here, we report the experimental evaluation of nine of the highest ranked drugs, confirming the accuracy of the model by showing an overall 9 ...[more]

PMID: 32235391

Similar Datasets

Project description:Background:Early and accurate diagnosis of malaria is critical to the success of malaria elimination. However, the current mainstay of malaria diagnosis in the field, such as light microscopy and rapid diagnostic tests (RDTs), have limitations due to low parasite density or mutation in diagnostic markers. Methods:We evaluated an inexpensive, robust, rapid, malaria diagnostic device, called Gazelle, that employs magneto-optical detection to identify haemozoin crystals (Hz) produced by all species of human malaria parasites in infected individuals. A beam of polarised light is passed through the lysed diluted blood sample under the influence of high (~.55T) and low magnetic fields. The difference in light transmission through the sample between the high and low magnetic fields indicates presence of Hz, suggesting possible malarial infection. A total of 300 febrile patients were screened at the malaria clinic of Indian Council of Medical Research-National Institute of Research in Tribal Health (ICMR-NIRTH), Jabalpur, India, from August 2018 to November 2018. Malaria diagnosis was done using four diagnostic methods: Gazelle, light microscopy, RDT, and malaria specific Polymerase Chain Reaction (PCR). Measures of diagnostic accuracy were compared. Findings:Out of 300 febrile patients enroled and tested for the presence of malaria parasites, 262 patient samples were included in the final analysis. The sensitivity and specificity of Gazelle was 98% and 97% in comparison to light microscopy, 82% and 99% to PCR and 78% and 99% to RDT, respectively. The results of the four diagnostic methods were comparable and statistically no significant differences in sensitivity or specificity was observed between these methods. Enhanced diagnostic accuracy of Gazelle in malaria patients with no prior history of malaria treatment was observed in this study. Interpretation:The diagnostic ability of Gazelle was comparable to light microscopy and better than RDTs even in low parasitemia and in presence of pfhrp2/3 deletion mutant parasites. Gazelle may be a novel valuable diagnostic tool in resource poor settings where (i) microscopy is not feasible and (ii) pfhrp2/3gene deleted parasite are present. Its speed, cost-efficiency, and alternative to lack of microscopists makes it an important adjunct in field settings. Funding:HemexDx, India.

Dataset Information

Lapatinib, Nilotinib and Lomitapide Inhibit Haemozoin Formation in Malaria Parasites.

Publications

Lapatinib, Nilotinib and Lomitapide Inhibit Haemozoin Formation in Malaria Parasites.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets