Fueling open-source drug discovery: 177 small-molecule leads against tuberculosis

Abstract

With the aim of fuelling open-source, translational, early-stage drug discovery activities, the results of the recently completed antimycobacterial phenotypic screening campaign against Mycobacterium bovis BCG with hit confirmation in M. tuberculosis H37Rv were made publicly accessible. A set of 177 potent non-cytotoxic H37Rv hits was identified and will be made available to maximize the potential impact of the compounds toward a chemical genetics/proteomics exercise, while at the same time providing a plethora of potential starting points for new synthetic lead-generation activities. Two additional drug-discovery-relevant datasets are included: a) a drug-like property analysis reflecting the latest lead-like guidelines and b) an early lead-generation package of the most promising hits within the clusters identified.

Figure 1

Plot of pIC₅₀ BCG versus pIC₅₀ HepG2: compounds were ranked according to therapeutic index [T.I.=(IC₅₀ HepG2)/(IC₅₀ BCG)]. According to the criteria established (T.I.>50), 960 compounds were selected for evaluation in H37Rv.

Figure 2

HTS progression cascade leading to 177 confirmed H37Rv-positive compounds.

Figure 3

Plot of pMIC H37Rv versus pMIC BCG: comparison of the H37Rv versus BCG activities of all active compounds from the BCG screen. Although a large number of BCG-selective compounds were found (vertical cluster at left, pMIC H37Rv=5.0), many hits displayed good activities in both species.

Figure 4

Most promising families from the HTS campaign: seven chemical families and one potent singleton selected from the 177 H37Rv hits for complete biological profiling. Full data are listed in Table 1.

Figure 5

Plot of calculated chromatographic log D_7.4 versus calculated molar refraction (CMR). Grey crosses represent marketed drugs with >30 % oral bioavailability, black crosses <30 % oral bioavailability, and the “TB set” as black circles. The line represents a discriminator between likely good and bad permeability. The chromatographic log D scale gives values approximately two units higher than the traditional distribution values assessed in octanol/water.