Designed for discovery of novel antibacterials
28 831 compounds
Despite extensive research in the antibacterial field, need of new effective and safe treatment remains one of the most important tasks in nowadays drug discovery. During the last decades, many investigations on antibacterials led to the systematic research and emergence of special rules in molecular parameters and structural features. Molecules with antibacterial activity are typically larger and more polar compering to the general drugs. Carefully collected available data was used for construction of our new Antibacterial library.
To provide good outcome from HTS screenings we designed dedicated library that might ensure high quality of derived hits and easy tractability of follow-up chemistry. Hits identified from our libraries can be easily followed with analogs synthesis through REAL Database technology with up to 85% synthetic success rate. Using our screening libraries you can save on time and cost in hit-follow up:
- Hit Confirmation support – QC check, resupply from dry powders and freshly prepared solutions, HPLC repurification of samples if needed.
- Fast and affordable library synthesis of analogs from 284 000 in-stock building blocks.
- Computational and MedChem support enhanced with on-site ADME/T panel.
You have also an option to screen the library directly at Enamine. We will be happy to offer you discount on library cost depending on the collaboration scope.
Knowledge-based approach was mainly used in the construction of our new antibacterial library. Strict refinement with the right molecular parameters profile was the first and basic stage in library design. Then the substructure and shape-based searches were used for the selection of molecules with privileged cores, motifs and natural product-like scaffolds, which are known to be essential for antibacterial activity.
Structural fragments used for the selection:
- Dihydrofolate reductase inhibitors
- Sulfa drugs
The library perfectly matches the distribution of physicochemical properties of known antibiotics, which enhances hit finding probability in both target-directed and cell-based assays. Particular attention was paid to the problems of the cell penetration for Gram-negative pathogens where the compounds with only a very narrow distribution of molecular weights, lipophilicity, and polar surface area can effectively work.
Antibacterial drugs occupy a unique property space that is remarkably different compared to drugs from other therapeutic areas. This fact has been long recognized, and general rules such as Lipinski’s rules of five do not apply to these compounds. The major differences between antibacterial and other drugs are MW and lipophilicity (ClogD7.4, ClogP, number of H-donors and -acceptors, and relative PSA).
Compounds with activity against Gram-negative organisms must overcome further barriers to function, namely, the penetration of the outer lipid membrane and evasion of efflux pumps. These additional requirements appear to result in even more dissimilar physicochemical properties compared to the reference drug set, with a larger MW (but strict MW cutoff at 600) and an increase in polarity, as reflected by the low average ClogD7.4 value of -2.8 and doubled relative PSA. Both parameters are partially believed to be driven by the properties of porin proteins that serve as a major entry pathway in Gram-negative bacteria.
ClogD7.4 values plotted against MW for major classes of antibacterial compounds
Relative PSA against MW for major antibacterial classes