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It is generally accepted that chemical diversity leads to diversity in bioactivity, hence majority high-throughput screening screening (HTS) efforts utilize compounds that are selected for being as unlike each other as possible. Highly diverse, optimized compound libraries improve the success of HTS by minimizing false positives and maximizing hit rates without significant increase in the library size.
Covalent inhibitors targeting enzymes such as kinases or proteases for a long time were set aside due to the high reactivity and potential toxicity. However, covalent kinase inhibitors were recently successfully introduced as cancer therapeutics agents. Thus, the benefits of irreversible kinase inhibition appeared to surpass the potential risks of such drugs. Traditionally, the most targeted residue in the protein kinase active site is cysteine. Due to the low abundance of this residue, drugs targeting cysteine appear to be more selective and have a lower chance of appearing to be toxic. All covalent enzyme inhibitors must contain specific reactive group (covalent "warhead"), and alternatively to cysteine, other amino acid residues were proposed as targets for reactive small molecules as well.
Scientific community studying medical chemicals has become increasingly aware of the value of the physical and structural properties of molecules. It is now known that the molecules which follow Lipinski's rule of five are more likely to appear biologically active. Other thresholds for properties were also proposed, for example, topological polar surface area and rotatable bonds number. Following the work of Frank Lovering et al. "Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success", which discovers saturation of chemical compounds as the measure of the likelihood of compounds to be biologically active, we created a library which comprises known thresholds of medical compounds and also contains highly saturated compounds.
Fundamental physico-chemical features required for optimal brain exposure of successful CNS drugs have been extensively studied in an attempt to define the attributes related to their ability to penetrate the blood-brain barrier (BBB) and exhibit CNS activity. On the other hand, BBB penetration may be a liability for many of the non-CNS drug targets, and a clear understanding of the physicochemical and structural differences between CNS and non-CNS drugs may assist both research areas.
Even though the chemical structures of drugs can differ greatly (in accordance with the requirement of complementary interactions to diverse target receptors), successful drugs on the market today do share certain similarities in their physicochemical properties. Perhaps the most well-known study in this area is the work of Lipinski and coworkers, who performed a statistical analysis of ~2,200 drugs from the World Drug Index. They established a set of heuristics that appears to be generally valid for the majority of the drugs considered in the study.
