Drug design Flashcards
List the approaches to discover an active drug
Serendipity – chance discovery by screening all available drug-like compounds from all sources (natural or synthetic) for biological activity against all targets using appropriate biological assays and High Throughput techniques.
Ligand/Structure based design – design of drugs based around the modification of natural ligands of the drug targets e.g. receptor ligand (agonist / antagonist), enzyme substrate or natural inhibitor (often computer aided, aka: CADD)
List the two diverse approaches are recognised for drug discovery;
phenotypic drug discovery and target directed discovery.
Facts about Phenotypic Drug Discovery
Targets are unknown.
Ideally use native human cells.
Assay throughput is usually low.
Screens used to measure the desired biological effect in cells, tissues or whole organisms where multiple, biologically relevant targets and pathways are simultaneously interrogated.
Need to do target deconvolution (enhance recorded data) to identify target.
Facts about Target Directed Discovery
Targets are identified and validated.
Typically use recombinant proteins or cells over-expressing the target of interest.
Assay throughput is usually high.
Screens used are to measure a compound’s effect on the target of interest.
Need to confirm compound effects in a relevant biological assay.
Options for screening for an active compound
Computer molecular modelling
High-throughput screening
Fragment screening (can involve crystallography expertise)
Knowledge-based design (medicinal and computational expertise and using existing published patents and literature)
Target validation, especially for new targets, is aimed at
gathering detailed background information and can involve a number of techniques focusing on effectiveness of a drug on a target for its therapeutic efficacy within appropriate safety limits.
Techniques used include,
e.g. gene expression profiling, using disease animal models, use of specific compounds that are inhibitors (various types) or activators, test for specific biomarkers, cell bioassays, and genetic manipulation (in vivo/in vitro). This aids with drug development and pathogenesis of the disease, and potentially saves time with drug development.
Facts about combinatorial synthesis
The basis of this approach is to make hundreds or more of novel molecules in relatively less time than to synthesise each one separately. The reactions are carried out on solid resin beads made up of polymers. The beads are not solid, but swell in solvents to provide spaces between the polymer chains where solvent and reagents are able to move around the extensive surface area.
The polymer chains have ‘anchor/linkers’, a functional group as a starting point. As groups are attached, the beads would be split up into groups and different chemical entities added to provide variation with final sequence of the compounds.
Advantages of combinatorial synthesis
Create a large range of molecules that can be screened effectively.
Increase probability of finding a compound with the desired therapeutic properties.
Process can be robotised for efficiency.
Facts about High Throughput Screening -
HTS is used to for identifying lead compounds that have therapeutic potential with minimal side effects. Large number of compounds are screened in a number of bioassays, often disease focused. This is often linked to combinatorial synthesis of compounds.
Initial primary screening identifies potential bioactive compounds, thereafter secondary screening using a fixed concentration to confirm the activity (remove false positives), specificity and compare potency. The potential compounds are then examined and accessed further as a hit to lead process. Common structural features are identified and a variety of related compounds with the essential structural features synthesised. These are tested for structure-activity relationships (SAR) in terms of chemical properties, specificity for the target and pharmacokinetics.
The next stage is lead optimisation, is prior to the clinical trials and involves monitoring parameters for ADMET and making chemical modifications for better absorption and reduced toxicity. Computer modelling may be included to aid with designing a better molecule. Various biochemical and cell-based assays, and in vivo models are utilised.
Facts about Hit-to-Lead
The above options can provide possible drug candidates that can be then explored further to find the most therapeutic advantageous molecule – lead optimisation.
Lead optimisation involves chemical modification of the lead molecule; prepare analogues for further testing. The aim is to reduce side effects (improve specificity), improve potency and physico-chemical properties, and give consideration to pharmacokinetic parameters/ADME. Subsequently, within the development process, clinical trials and type of patient to involve, how the drug is to be formulated, administration options and large scale manufacturing process.
Current Trends in Drug Development
It can take as long as 10-12 years from discovery to a drug ready for patient use. Hence, aim has been to reduce this time scale and it has been possible to an extent by:
i, use cloned human targets,
ii, high-throughput screening of large number of compounds to find the lead,
iii, lead optimisation by using automated synthesis to produce a large number of related compounds,
iv, virtual screening of large number of compounds by molecular modelling,
v, consider pharmacokinetics aspects (e.g. absorption profile, half-life, metabolism, accumulation of the
drug in tissues) and toxicity consideration early during the lead optimisation stage.
