Cheminformatics Models for Inhibitors of Schistosoma mansoni

Schistosomiasis is a neglected tropical disease caused by a parasite Schistosoma mansoni and affects over 200 million annually. There is an urgent need to discover novel therapeutic options to control the disease with the recent emergence of drug resistance. The multifunctional protein, thioredoxin glutathione reductase (TGR), an essential enzyme for the survival of the pathogen in the redox environment has been actively explored as a potential drug target. The recent availability of small-molecule screening datasets against this target provides a unique opportunity to learn molecular properties and apply computational models for discovery of activities in large molecular libraries. Such a prioritisation approach could have the potential to reduce the cost of failures in lead discovery. A supervised learning approach was employed to develop a cost sensitive classification model to evaluate the biological activity of the molecules. Random forest was identified to be the best classifier among all the classifiers with an accuracy of around 80 percent. Independent analysis using a maximally occurring substructure analysis revealed 10 highly enriched scaffolds in the actives dataset and their docking against was also performed. We show that a combined approach of machine learning and other cheminformatics approaches such as substructure comparison and molecular docking is efficient to prioritise molecules from large molecular datasets

Streptococcal dTDP-L-rhamnose biosynthesis enzymes:functional characterization and lead compound identification

Biosynthesis of the nucleotide sugar precursor dTDP-L-rhamnose is critical for the viability and virulence of many human pathogenic bacteria, including Streptococcus pyogenes (Group A Streptococcus; GAS), Streptococcus mutans and Mycobacterium tuberculosis. Streptococcal pathogens require dTDP-L-rhamnose for the production of structurally similar rhamnose polysaccharides in their cell wall. Via heterologous expression in S. mutans, we confirmed that GAS RmlB and RmlC are critical for dTDP-L-rhamnose biosynthesis through their action as dTDP-glucose-4,6-dehydratase and dTDP-4-keto-6-deoxyglucose-3,5-epimerase enzymes respectively. Complementation with GAS RmlB and RmlC containing specific point mutations corroborated the conservation of previous identified catalytic residues. Bio-layer interferometry was used to identify and confirm inhibitory lead compounds that bind to GAS dTDP-rhamnose biosynthesis enzymes RmlB, RmlC and GacA. One of the identified compounds, Ri03, inhibited growth of GAS, other rhamnose-dependent streptococcal pathogens as well as M. tuberculosis with an IC 50 of 120–410 µM. Importantly, we confirmed that Ri03 inhibited dTDP-L-rhamnose formation in a concentration-dependent manner through a biochemical assay with recombinant rhamnose biosynthesis enzymes. We therefore conclude that inhibitors of dTDP-L-rhamnose biosynthesis, such as Ri03, affect streptococcal and mycobacterial viability and can serve as lead compounds for the development of a new class of antibiotics that targets dTDP-rhamnose biosynthesis in pathogenic bacteria

Whole Genome Sequencing Variant Call Files for Trypanosoma brucei clones resistant to nifurtimox or fexinidazole

Genomic DNA prepared from parental and drug resistant clones from T.brucei was sequenced on an Illumina HiSeq 2000 sequencer. The Illumina data were aligned against the T.brucei TREU927 reference genome and variants were called using SAMtools v0.1.19 and BCF tools. The files are in variant call format listing all 190064 genomic positions at which any one of the six drug-resistant and the parental parasite lines had a variant call

Fragments and hot spots in drug discovery

R01 GM064700 - NIGMS NIH HHSPublished versio

Disruptive Strategies for Removing Drug Discovery Bottlenecks

Drug Discovery is shifting focus from the industry to outside partners and in the process creating new bottlenecks, suggesting the need for a more disruptive overhaul. Technologies like high throughput screening (HTS) have moved to a larger number of academic and institutional laboratories in the US, with little apparent coordination or consideration of the outputs and creating a translational gap. While there have been collaborative public private partnerships in Europe to share pharmaceutical data, the USA has lagged behind. Sharing precompetitive computational models may be the next frontier to provide more confidence in the quality of the leads produced and attract investment. We suggest there needs to be an awareness of what research is going on in the screening centers, more collaboration and coordination. These efforts will shift the focus to finding the best researchers to fund and require a rethink of how to reward their collaborative efforts

Drug Discovery

Natural products are a constant source of potentially active compounds for the treatment of various disorders. The Middle East and tropical regions are believed to have the richest supplies of natural products in the world. Plant derived secondary metabolites have been used by humans to treat acute infections, health disorders and chronic illness for tens of thousands of years. Only during the last 100 years have natural products been largely replaced by synthetic drugs. Estimates of 200 000 natural products in plant species have been revised upward as mass spectrometry techniques have developed. For developing countries the identification and use of endogenous medicinal plants as cures against cancers has become attractive. Books on drug discovery will play vital role in the new era of disease treatment using natural products

Bayer AG v. Housey Pharmaceuticals: Protection for Biotechnological Research Tools under Section 271(g) Found Wanting

[Excerpt] Research tools, a subset of biotechnological inventions protected by process patents, are “tools that scientists use in the laboratory, including cell lines, monoclonal antibodies, reagents, animal models, growth factors, combinatorial chemistry and DNA libraries, clones and cloning tools (such as PCR), methods, laboratory equipment and machines.” Many companies base their business models on the ability to find pharmaceutical products using their proprietary drug discovery research tools. Research tools used for drug discovery ‘include bioinformatic methods for identifying the interaction of certain proteins and their association with disease, methods for confirming protein targets, screening assays to identify molecules active against a target, and safety profiling assays.’