The library designed using common molecular parameters of antibacterial gruds, enriched with compounds similar to well known and highly potent actives
35 899 compounds
Despite intensive research in the antibacterial field, need of new effective and safe treatment remains the most important task. During the last decade, many investigations on antibacterials led to the systematic research and special rules in molecular parameters. Usually, molecules with antibacterial activity are larger and more polar compering to the general drugs. Careful analysis of available data allowed as to design
To design our new library of potential antibacterial agents we applied knowledge-based approach with the selection of molecules with the most similar molecular properties to known and validated antibiotics. A number of molecular parameters restrictions were used to extract the initial dataset. Then the substructure and shape-based searches were used for the selection of molecules with privileged cores and natural product-like scaffolds, which are known to be essential for antibacterial activity.
- 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). Drugs with activity only against Gram-positive bacteria have much less restriction in MW, especially if the target is located in the peptidoglycan matrix or on the outer surface of the underlying lipid bilayer and permeation through the inner lipid membrane is not required to kill the pathogens.
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.