Drug-like features

Hann et al. used a similar, multilevel approach when pooling compounds for HTS. These authors applied three types of filters. Basic filters were used to remove molecules with non-drug-like features. Next functional group-based hard filters were utilized... 

However the development of inhibitors for PTPs with suitable drug-like features of selectivity, absorption, distribution, metabolism, excretion and toxicity (ADMET) has proven to be challenging in part due to the highly conserved and charged active site [39]. A potent inhibitor of human low molecular weight protein tyrosine phosphatase is a 3-phenoxyphenyl derivative of an 5 -arylidene-2,4-thiazolidinedione [40]. 

As another example, from the Schmidt and Schultz laboratories, in a route amenable to smaller macrocyclic molecules with less peptidic character, the ribosomal peptide natural product pathway for cyanobactins was manipulated in a manner that permitted the incorporation of multiple non-proteinogenic amino acids. This produced structures, 307 (Figure 11.28) as a representative example, with rings as small as 18-membered and possessing more drug-like features. 

Neurodegeneration Localised or widespread death of neurons, a feature of a number of brain disorders, such as Alzheimer s disease, Parkinson s disease and cerebrovascular stroke. It can also be caused by neurotoxic drugs like MDMA/Ecstasy, although there is debate over whether this occurs in humans as well as laboratory animals. 

There are a variety of structural classes of compounds that are active against each phosphodiesterase, and evidence suggests that selective inhibitors of PDEs can be identified. The structural diversity of PDE inhibitors provides a multitude of opportunities for development of compounds with drug-like properties. Furthermore, phosphodiesterase inhibition, which avoids direct interaction of a compound with a cell surface or nuclear receptor, may circumvent some of the target selectivity issues that can complicate receptor-based therapeutic approaches. As noted above, the specific subcellular distribution of phosphodiesterase enzymes is a key feature of their ability to modulate intracellular signaling pathways. This localization of the enzyme may minimize non-specific target... 

Although, a small molecule cannot accommodate the large protein interface, yet the disruption of such interfaces by small drug-like molecules is possible (13, 59, 60). Particular features of the protein interface should be considered to make this possible (61). As seen above, the presence of hot spots, i.e., the presence of micro-cavities in which ligand atoms can interact very strongly is one of the most important criteria (62-67). 

The focus of this book is on methods and processes designed to predict drug-like properties, exposure and safety during hit and lead discovery. We do not intend to cover specific cultural considerations and marketing aspects [3]. What we will highlight is the need of a risk aware environment for drug discovery, where data-based integrated risk assessment is part of daily life of the team and drives the projects towards molecules with features fit for the description of an efficacious and safe medicine. 

Bemis and Murcko (10) analyzed known drugs in an effort to identify common features and scaffolds, which could be used to bias fragment libraries toward drug-like structures. An optimal molecular complexity was also discussed by Hann and coworkers... 

The desirability of a chemotype is a function of drug-likeness, potency, novelty, and analogability. A particularly attractive feature of combinatorial chemistry is that when desirable properties are identified, they can often be... 

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