The search for molecules with activity against Mycobacterium tuberculosis (Mtb) is employing many approaches in parallel including high throughput screening and computational methods. We have developed a database (CDD TB) to capture public and private Mtb data while enabling data mining and collaborations with other researchers. We have used the public data along with several cheminformatics approaches to produce models that describe active and inactive compounds. We have compared these datasets to those for known FDA approved drugs and between Mtb active and inactive compounds. The distribution of polar surface area and pKa of active compounds was found to be a statistically significant determinant of activity against Mtb. Hydrophobicity was not always statistically significant. Bayesian classification models for 220 463 molecules were generated and tested with external molecules, and enabled the discrimination of active or inactive substructures from other datasets in the CDD TB. Computational pharmacophores based on known Mtb drugs were able to map to and retrieve a small subset of some of the Mtb datasets, including a high percentage of Mtb actives. The combination of the database, dataset analysis, Bayesian and pharmacophore models provides new insights into molecular properties and features that are determinants of activity in whole cells. This study provides novel insights into the key 1D molecular descriptors, 2D chemical substructures and 3D pharmacophores which can be used to mine the chemistry space, prioritizing those molecules with a higher probability of activity against Mtb.

There is an urgent need for new drugs against tuberculosis which annually claims 1.7-1.8 million lives. One approach to identify potential leads is to screen in vitro small molecules against Mycobacterium tuberculosis (Mtb). Until recently there was no central repository to collect information on compounds screened. Consequently, it has been difficult to analyze molecular properties of compounds that inhibit the growth of Mtb in vitro. We have collected data from publically available sources on over 300 000 small molecules deposited in the Collaborative Drug Discovery TB Database. A cheminformatics analysis on these compounds indicates that inhibitors of the growth of Mtb have statistically higher mean logP, rule of 5 alerts, while also having lower HBD count, atom count and lower PSA (ChemAxon descriptors), compared to compounds that are classed as inactive. Additionally, Bayesian models for selecting Mtb active compounds were evaluated with over 100 000 compounds and, they demonstrated 10 fold enrichment over random for the top ranked 600 compounds. This represents a promising approach for finding compounds active against Mtb in whole cells screened under the same in vitro conditions. Various sets of Mtb hit molecules were also examined by various filtering rules used widely in the pharmaceutical industry to identify compounds with potentially reactive moieties. We found differences between the number of compounds flagged by these rules in Mtb datasets, malaria hits, FDA approved drugs and antibiotics. Combining these approaches may enable selection of compounds with increased probability of inhibition of whole cell Mtb activity.