Chemistry Reference
In-Depth Information
Important aspects of protein-ligand binding interactions can be addressed by using
pharmacopheres (from three-dimensional structures of proteins). Compounds that
do not have importance for binding structural or molecular properties can be
removed. In order to find new leads we can use pharmacopheres (encoding
essential, key, conserved features) followed by workflows with a narrower
selection. In order to search for selective features/profile (excluded volumes, less
conserved portions of binding site, specific intermolecular interactions) we may
need more crystal structures with specific ligand features.
It may also be important to evaluate ADMET, biological and physicochemical
properties at an early stage in the virtual screening process filtering out
compounds (with poor drug-like and unfavorable, pharmacokinetic properties). It
may also be necessary to filter out interfering properties for
in vivo
and
in vitro
experiments, highly reactive groups, promiscuous compounds, poor solubility/
absorption/ permeation as well as interference with accurate biological activity).
Simple rules are available for drug and lead identification. Modeling of ADMET
properties and pharmacological similarity will play important roles in chemical
library design and screening. It is expected that future increased integration of
ADMET properties in virtual screening will improve the quality of generated hits.
There is also increasing interest in predicting drug repositioning as well as multi
target/off-target activities. It is necessary to provide a good comprehensive
framework of pharmacological, chemical and biological information on drugs
(small drugs in particular) for virtual screening. Removing from the libraries
compounds with similar structures (differing by isosteric replacements,
substituents) will increase their chemical diversity. In some cases, however, it
may be necessary to restrict chemical diversity to specific classes of compounds.
It is noteworthy that undesirable ADMET properties and difficult synthetic
schemes can hinder virtual screening follow-up procedures. Solutions/suggestions
could include virtual synthesis, retrosynthetic schemes, diversity-oriented
synthesis, biologically oriented synthesis, click-type assembly of ligands into the
protein binding site. Using novelty and chemical diversity criteria for assembling
