AUTOSTERE: Systematic Search for Scaffold Replacement Opportunities within Structural Databases.

Medicinal chemists often bias toward working with scaffolds with which previously they have had direct experience and successes. In this way, it is often the case that scaffolds which have proven tractable within a research group are "reused" across multiple and sometimes unrelated drug targets. With this concept in mind, we designed a new computer algorithm AUTOSTERE which could systematically assess the opportunities to replace any part of any molecule within an entire database of known ligand structures with a target scaffold and automatically evaluate the potential designs in the context of the original ligand's protein environment. As such, it performs scaffold replacement on an unprecedented scale and suggests new target opportunities for preferred chemistries rather than the conventional reverse situation. The results of this approach for one scaffold, a substituted triazolinone, applied to a set of 10 426 ligand conformations extracted from the PDB are described. This led to the identification of ∼600 novel ligands incorporating the triazolinone scaffolds in complex with their predicted drug targets. From these, design examples are provided for HSP-90, cathepsin K, and TIE-2 kinase. A further study involved the searching for possible drug targets for unusual pyridopyrimidine cores. This process resulted in the identification of potential novel HIV reverse transcriptase inhibitors which were synthesized and shown to exhibit similar in vitro potencies to marketed compounds. Overall, the methodology described provides a powerful new approach to identify new target opportunities for scaffolds of provenance.

Synthesis of novel PPARα/γ dual agonists as potential drugs for the treatment of the metabolic syndrome and diabetes type II designed using a new de novo design program PROTOBUILD.

Peroxisome proliferator activated receptors (PPARs) have been shown to have critical roles in fatty acid oxidation, triglyceride synthesis, and lipid metabolism - making them an important target in drug discovery. Here we describe the in silico design, synthesis and in vitro characterisation of a novel series of 2,5-disubstituted indoles as PPARα/γ dual agonists. PPAR activation assays are performed with known agonists diazabenzene (WY14.643), aminopyridine (BRL49653) and bisaryl (L165.041), as positive controls. All the indole compounds synthesized are found to be active PPARα and PPARγ agonists, with particular efficacy from those with 2-naphthylmethyl substitution. This is a useful demonstration of a new de novo design methodology implemented by the protobuild program and its ability to rapidly produce novel modulators for a well characterized drug target.

An inhibitor of FtsZ with potent and selective anti-staphylococcal activity.

FtsZ is an essential bacterial guanosine triphosphatase and homolog of mammalian beta-tubulin that polymerizes and assembles into a ring to initiate cell division. We have created a class of small synthetic antibacterials, exemplified by PC190723, which inhibits FtsZ and prevents cell division. PC190723 has potent and selective in vitro bactericidal activity against staphylococci, including methicillin- and multi-drug-resistant Staphylococcus aureus. The putative inhibitor-binding site of PC190723 was mapped to a region of FtsZ that is analogous to the Taxol-binding site of tubulin. PC190723 was efficacious in an in vivo model of infection, curing mice infected with a lethal dose of S. aureus. The data validate FtsZ as a target for antibacterial intervention and identify PC190723 as suitable for optimization into a new anti-staphylococcal therapy.

Surface runoff water quality in a managed three zone riparian buffer.

Managed riparian forest buffers are an important conservation practice but there are little data on the water quality effects of buffer management. We measured surface runoff volumes and nutrient concentrations and loads in a riparian buffer system consisting of (moving down slope from the field) a grass strip, a managed forest, and an unmanaged forest. The managed forest consisted of sections of clear-cut, thinned, and mature forest. The mature forest had significantly lower flow-weighted concentrations of nitrate, ammonium, total Kjeldahl N (TKN), sediment TKN, total N (nitrate + TKN), dissolved molybdate reactive P (DMRP), total P, and chloride. The average buffer represented the conditions along a stream reach with a buffer system in different stages of growth. Compared with the field output, flow-weighted concentrations of nitrate, ammonium, DMRP, and total P decreased significantly within the buffer and flow-weighted concentrations of TKN, total N, and chloride increased significantly within the buffer. All loads decreased significantly from the field to the middle of the buffer, but most loads increased from the middle of the buffer to the sampling point nearest the stream because surface runoff volume increased near the stream. The largest percentage reduction of the incoming nutrient load (at least 65% for all nutrient forms) took place in the grass buffer zone because of the large decrease (68%) in flow. The average buffer reduced loadings for all nutrient species, from 27% for TKN to 63% for sediment P. The managed forest and grass buffer combined was an effective buffer system.