Abstract
BackgroundIn view of the need to continuously feed the pipeline with new anti-malarial agents adapted to differentiated and more stringent target product profiles (e.g., new modes of action, transmission-blocking activity or long-duration chemo-protection), a chemical library consisting of more than 250,000 compounds has been evaluated in a blood-stage Plasmodium falciparum growth inhibition assay and further assessed for chemical diversity and novelty.MethodsThe selection cascade used for the triaging of hits from the chemical library started with a robust three-step in vitro assay followed by an in silico analysis of the resulting confirmed hits. Upon reaching the predefined requirements for selectivity and potency, the set of hits was subjected to computational analysis to assess chemical properties and diversity. Furthermore, known marketed anti-malarial drugs were co-clustered acting as ‘signposts’ in the chemical space defined by the hits. Then, in cerebro evaluation of the chemical structures was performed to identify scaffolds that currently are or have been the focus of anti-malarial medicinal chemistry programmes. Next, prioritization according to relaxed physicochemical parameters took place, along with the search for structural analogues. Ultimately, synthesis of novel chemotypes with desired properties was performed and the resulting compounds were subsequently retested in a P. falciparum growth inhibition assay.ResultsThis screening campaign led to a 1.25% primary hit rate, which decreased to 0.77% upon confirmatory repeat screening. With the predefined potency (EC50 < 1 μM) and selectivity (SI > 10) criteria, 178 compounds progressed to the next steps where chemical diversity, physicochemical properties and novelty assessment were taken into account. This resulted in the selection of 15 distinct chemical series.ConclusionA selection cascade was applied to prioritize hits resulting from the screening of a medium-sized chemical library against blood-stage P. falciparum. Emphasis was placed on chemical novelty whereby computational clustering, data mining of known anti-malarial chemotypes and the application of relaxed physicochemical filters, were key to the process. This led to the selection of 15 chemical series from which ten confirmed their activity when newly synthesized sample were tested.
Highlights
In view of the need to continuously feed the pipeline with new anti-malarial agents adapted to differentiated and more stringent target product profiles, a chemical library consisting of more than 250,000 compounds has been evaluated in a blood-stage Plasmodium falciparum growth inhibition assay and further assessed for chemical diversity and novelty
Campaign, and was an attractive hit molecule based on low molecular weight and, a high Ligand Efficiency Index (LEI)
The compound significantly degraded upon standing at room temperature to the dimer 2 (Figure 8). This compound showed an EC50 in the same range as initially described during the high throughput screening (HTS), suggesting that the original compound sample had degraded over time. Due to this obvious chemical instability, indole derivative 1 did not qualify as a hit. 3, is a structurally simple molecule, comprised of two amide bonds and a primary amine group, which post synthesis demonstrated a significant decrease in activity from an initial EC50 of 222 nM (P. falciparum 3D7) to 3 μM (P. falciparum NF54). 4 (Cluster 38) has an indoline core with two adjacent stereocentres and was originally tested at HTS as a potential mixture of four diastereomers
Summary
In view of the need to continuously feed the pipeline with new anti-malarial agents adapted to differentiated and more stringent target product profiles (e.g., new modes of action, transmission-blocking activity or long-duration chemo-protection), a chemical library consisting of more than 250,000 compounds has been evaluated in a blood-stage Plasmodium falciparum growth inhibition assay and further assessed for chemical diversity and novelty. Following the discovery in 1880 of the eukaryote parasite of the genus Plasmodium in the red blood cells of malaria patients by the French military doctor, Laveran, malaria remains a widespread tropical disease that affects approximately 207 million people mainly in developing countries. Much progress has been made in understanding the biology of the parasite lifecycle and mode of transmission, significant challenges still remain, in order to eradicate malaria, for which new therapeutic agents, as well as transmission and vector control will be needed [3]
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