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 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 93% hit rate. Lapatinib, nilotinib, and lomitapide showed the best activity for inhibition of β-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 β-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.
Highlights
Malaria is an infectious tropical disease caused by five human-infecting species of Plasmodium parasites that remain a major public health problem with a severe socio-economic impact, despite recent successes in control and eradication
The previously highly successful drug chloroquine (CQ), which is no longer recommended for the treatment of P. falciparum infections because of widespread resistance, has a mechanism of action based on inhibition of the parasite haem detoxification process
We further investigated the United States Food and Drug Administration (USFDA) approved drugs, starting with those that were highest ranked in the Bayesian model as potential β-haematin inhibitors bioactive against P
Summary
Malaria is an infectious tropical disease caused by five human-infecting species of Plasmodium parasites that remain a major public health problem with a severe socio-economic impact, despite recent successes in control and eradication. We reported the first structure-based virtual screening using the β-haematin crystal as a target by applying a docking method This made use of the ZINC15 database, a subset of which was searched for compounds with high binding affinity with the surface of the β-haematin crystal. We evaluate the performance of the SBVS method that we recently reported [13], using the USFDA approved drugs This compound set was screened for binding to the β-haematin crystal and the top ranked drugs tested in a β-haematin inhibition assay. Nilotinib, and lomitapide showed the best activity for inhibition of both β-haematin formation and parasite growth As a consequence, they were chosen to conduct a cellular haem fractionation assay to measure free haem and haemozoin in cultured P. falciparum cells as a function of dose. They showed an overall β-haematin inhibition hit rate of 6.9%, representing a significant enrichment over random HTS
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