Integrated dataset of screening hits against multiple neglected disease pathogens

Abstract

New chemical entities are desperately needed that overcome the limitations of existing drugs for neglected diseases. Screening a diverse library of 10,000 drug-like compounds against 7 neglected disease pathogens resulted in an integrated dataset of 744 hits. We discuss the prioritization of these hits for each pathogen and the strong correlation observed between compounds active against more than two pathogens and mammalian cell toxicity. Our work suggests that the efficiency of early drug discovery for neglected diseases can be enhanced through a collaborative, multi-pathogen approach.

Figure 1. LifeChemicals library calculated properties analysis.

A: Histograms representing calculated PSA, molecular weight (MW), aLogP and LogD for the selected Life Chemicals screening set. Overall, the library respects the criteria for the rule of five (maximum acceptable of each criteria represented by the vertical red line) except the PSA which has a slightly high calculated index. B: This grap is summarizing the Principal Component Analysis (PCA) of screened library versus PCA of DrugBank library. The DrugBank database is a resource that contains detailed data for about 6800 drugs. Calculated PCA show that the Life Chemical library (represented by the red ellipsis) sits within the 95% PCA confidence index of the DrugBank library (represented by the blue ellipsis). The PCA calculation was based on the descriptors to account for size, flexibility and polarity of molecules (molecular weight [size], number of rotatable bonds [flexibility], hydrogen bond acceptors [molecular polarity], hydrogen bond donors [molecular polarity], topological polar surface area [molecular polarity] and ALogP [molecular polarity].

Figure 2. Screening logistics and framework.

The formatting and distribution of the library to various screening centers on dry ice was handled by 2 screening partners - Laboratory for Microbiology, Parasitology and Hygiene at the University of Antwerp (LMPH) and the London School of hygiene and Tropical Medicine (LSHTM). Two shipments were lost (indicated by dark grey boxes) due to logistics problems. Considering the high variability of screening throughput (P. falciparum = 100,000 compounds/month, T. cruzi, T. brucei & L. infantum = 10,000 compounds/month, while S. mansoni (adult worms), B. malayi (adult worms and microfilaria) and O. lienalis/O. ochengi (microfilaria) = 1,000 compounds/month), shipments were handled in 3 batches from increasing size. For batch 2 and 3 and for diseases having 2 different screening sites (Schistosomiasis with London School of Hygiene and Tropical Medicine (LSHTM) and Theodor Bilharz Institute (TBRI) in Cairo or Onchocerciasis with Northwick Park Institute for Medical Research (NPIMR) using O. lienalis and the University of Buea (UB) using O. ochengi) it was decided to have molecules individually tested on one single site.

Figure 3. Comparison of the 744 hits from different pathogens and cytotoxicity.

The 744 hits identified on the various pathogens are sorted by compound identifier (ID). Each colored line represents an active molecule and each column represents an assay for a pathogen or cytotoxicity (C = cytotoxicity, M = malaria, H = HAT, CD = Chagas disease, L = Leishmaniasis, S = Schistosomiasis, LF = Lymphatic Filariasis (microfilaria) and O = Onchocerciasis (microfilaria). Except for cytotoxicity, where active molecules are highlighted in red (activity<1 µg/ml), orange (1 µg/ml75% motility reduction at 12.5 µM) are highlighted in yellow. Grey box represent missing results. Further details on color coding are available below.

Figure 4. Comparison of Chagas (T. cruzi) and HAT (T. brucei) hits that are non cytotoxic.

Graph show IC₅₀ values of all non cytotoxic compounds (IC₅₀>5 ug/ml on MRC5 cells) on Chagas (X axes) and on HAT (Y axes). Interesting series are grouped into 3 sub groups as follows: 1) the compounds that are active against only T. cruzi are represented by large light blue squares around the Y axes, 2) the compounds active against only T. brucei are represented by small dark blue squares around the X axes, and 3) compounds active against both pathogens identified as large dark blue close to the cross axes. The compounds in group 3 are potential candidates for joint development for the 2 diseases.