The Medicinal Chemistry Core is fully equipped to support:
- High-throughput screening outcome triage
- High-throughput screening (HTS) is a method used in drug discovery and related fiields of research. Using robotics and the appropriate software, high-throughput screening allows a researcher to quickly conduct large numbers of in vitro assays against large libraries of distinct chemical entities to identify active compounds, that modulate a molecular pathway. The collection of total HTS "hits" represents a starting point for HTS triage. Compounds or series of compounds are prioritized based on biochemical (promiscuity, structural alerts, etc.) and physciochemical properties (MW, cLogP, solubility, structural complexity, rule-of-5-compliance, etc). The outcome of HTS traige is the identification of 1-3 compounds / series for further manipulation via synthesis or catalog purchases and would represent the initiation of lead development. or could be starting points for drug design and for understanding the interaction or role of a particular biochemical process in biology.
- Lead development
- Lead development requires identification of a lead small molecule from HTS screening or similar with potential to be made into a clinical candidate. Once identified, the chemical structure of the lead compound is chemical modified to improve potency, selectivity or pharmacokinetic (PK) parameters.
- Scaffold-hopping in drug-design is widely used in drug discovery. Scaffold-hopping requires an active molecule with either an experimentally determined, or a hypothetical, binding conformation. A central part or a portion of the molecule is then replaced by a new scaffold which is able to retain the original binding groups of the molecule in their optimized binding orientation. The process allows for the identification of new scaffolds which might impart better physicochemical properties or avoid existing patent art.
- Structure-based design
Structure-based drug design is dependent on having knowledge of the three dimensional structure of the biological target obtained through methods such as x-ray crystallography or NMR spectroscopy. Using the structure of the biological target, compounds are predicted to bind with high affinity then and prepared synthetically. Selectivity may also be designed into a molecule using this process. Both are designed using interactive graphics and the chemical intuition.
Current methods for structure-based drug design can be divided roughly into three main categories.
The identification of new ligands for a given receptor by searching databases of 3D structures (virtual screening) of small molecules to find those fitting the binding pocket of the receptor.
de novo design of new ligands built up within the constraints of the binding pocket by assembling small pieces in a stepwise manner.
The optimization of known ligands by the evaluation and prioritization for synthesis of proposed analogs within the binding cavity.
- Structure activity relationship (SAR) development
- A structure–activity relationship (SAR) is the relationship between the chemical or 3D structure of a molecule and its biological activity. The analysis of SAR enables the determination of the chemical group or substitution responsible for a biological effect. The developed understanding allows further modulation of the effect of a bioactive compound by changing its chemical structure. Chemical synthesis is used to insert new chemical groups and test the modifications for their biological effects.
- Route development
- Active Pharmaceutical Ingredient
- Traditional organic synthesis (mg to 200 g scale)
- Peptide synthesis
- Parallel medicinal chemistry methods