Integrated drug discovery at SARomics Biostructures

Computational Chemistry in Drug Design

1. Hit identification

When planning a drug discovery project we need to take into consideration several factors. The image below summarizes the possible scenarios:

• The first factor is the availability of a protein structure: A known structure will facilitate the whole process and will allow the use of structure-based drug design tools, the most important of which at the initial stages is probably computational chemistry, which includes virtual library design,
in silico (virtual) screening, docking, scoring, etc. The result of this process is a series of hit compounds with the highest docking scores.

• The second factor to take into consideration is the availability of ligands, known to bind to the protein in question. The most preferable is of course an atomic structure of the complex of the ligand with the protein. Such structure will clearly define the ligand binding site, the types of interactions present there (hydrogen bond interactions, the presence of a hydrophobic pocket, the protein residues involved in these interactions, etc.). This information will allow a reliable construction of a structure-based
pharmacophore model (originally introduced in 1909 by Ehrlich), which is required in the preparation for virtual screening, de novo design or lead optimization (a pharmacophore is a set of structural features that are recognized at the binding site and are responsible for the biological activity of the compound, for details see also Yang, Drug Discov Today).

With a known protein and ligand structure we are in the blue quadrant in the image below - the requirements for a structure-based drug design are fulfilled. Our virtual library contains millions of purchasable compounds. It has already been pre-filtered to remove e.g. reactive groups and too-lipophilic compounds. The libraries used may also be designed to contain, for example, drug-like molecules, natural compounds, or small-fragment molecules. After a virtual screening campaign hits are clustered to aid the selection of compounds to rapidly purchase and test. After testing a follow up
in silico similarity search is performed in order to purchase similars of the identified active molecules. This offers the fastest possible establishment of a SAR (structure-activity relationships).

In case there is no experimental structure of the target, SARomics Biostructures offers gene-to-drug services. In this case the protein is cloned, expressed, purified and crystallized and its three-dimensional structure is determined at the company.

Computational chemistry and dtructure-based drug discovery

2. Hit expansion, lead generation and optimization
Compounds identified using
in silico screening are subsequently verified in activity assays using assay capabilities of our partner Red Glead.
In our experience, virtual screening substantially increases hit rates in subsequent activity assays. To filter out false positives, we also assess the binding of the identified compounds using biophysical screening methods, like Nuclear Magnetic Resonance (NMR), thermal-shift assay and finally X-ray crystallography. This step is particularly important in the case of fragment screening, since the frequency of false positives tends to be high for fragments, which are screened at relatively high concentrations.
The three-dimensional structure of the protein-ligand complex helps to reveal the details of protein-ligand interactions, enabling rational expansion and linking of identified hits, further optimization of the chemistry and physical-chemistry characteristics of the compounds. Multiple protein-ligand complexes also help in detailed mapping of the binding site and in improving the pharmacophore model, which in turn may be used in the design of new focused compound libraries and new screens. Optimization of ligand structure should result in improving its binding affinity and other properties, a process which may take several cycles. The result may be a series of compounds, which after further optimization and tests will result in a lead molecule.
As part of our
custom protein crystallography services, SARomics Biostructures also offers protein-ligand co-crystallization with customer's compounds.
SARomics Biostructures
Integrated drug discovery services are usually adapted to the needs of each projects and the requirements of our customers. Please contact us to discuss your project.