Drug design
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Transcript of Drug design
Molecular descriptorsNumerical values that characterize properties of molecules
They may represent • The physicochemical properties of a Molecule
• The values that are derived by applying algorithmic techniques to the molecular structures
Molecular descriptorsThey vary in the complexity of the information they encode and in the time required to calculate them
Computational requirements increase with the level of discrimination
Some descriptors have an experimental counterpart (logP),whereas others are purely algorithmic constructs (2D fingerprinters )
2D descriptorsDescriptors calculated from the 2D structure
1. Simple counts: -H-bond donors
-H-bond acceptors
-Ring systems
-Rotatable bonds
-Molecular weight
3D descriptors
1.3D fragment screensThese encode spatial relationships (e.g. distances & angles) between the different features of a molecule such as atoms, ring centroids and planes
2.Pharmacophore Keys
DrugIn pharmacology, “A chemical substance used in the treatment, cure, prevention, or diagnosis of disease or used to otherwise enhance physical or mental well-being”
How can drugs be designed?Traditional approach: Screening approach• Trial and error as molecular mechanisms of disease not known•Time-consuming, laborious
Deterministic approach (Rational drug design)• Identify molecular target critical to the disease (host or pathogen)•Prepare and screen inhibitory compounds•Success depends on high-resolution, accurate structure of molecule
Molecular basis of Drug specificity
Molecular specificity involves
• Binding of drug to target with suitable affinity (High affinity = Low doses, fewer side effects)
•Affect activity of the target
Proteins as Targets of drugs
Proteins are the cellular targets of many drugs.Proteins can be • Cytosolic• Membrane bound
Depending on the location of the protein, drugs need to • enter into cells• bind to an extracellular domain and affect intracellular processes
Rational drug design
Application of biocomputing in drug design/discovery
• Optimize the pharmacological profile of existing drugs by predicting structure and properties of new compounds
• Use the available structural information on possible protein targets and their biochemical role in the cell to develop novel therapeutic concepts
Structure-based drug design
3D structure of a drug target interacting with small molecules is used to guide drug discovery
Powerful Slow and not reliable Designed molecules were good inhibitors in vitro, but did not
work well as drugs
Combinatorial Chemistry
Strategy: Make a lot of molecules with combinatorial chemistry and devise rapid tests for utility
Process: Take a small number of starting compounds and react them with a larger number of reagents
Ligand-based drug design
Pharmacophore: A set of structural features in a molecule that is recognized at a receptor site and responsible for that molecule’s biological activity
Typical features: Hydrophobic Aromatic H-bond acceptor H-bond donor Cationic or anionic moieties
Best strategy
Structure-based drug design coupled with combinatorial techniques
• Use structure to design basic skeleton• Synthesize combinatorial derivatives• Test empirically for activity or binding• Analyze crystal structures of best ligands• Refine predictions to get better molecule• Second round of combinatorial synthesis
QSAR
Quantitative structure-activity relationships (QSAR) Represent an attempts to correlate structural or property descriptors of compounds with activities
Activities used in QSAR include chemical measurements and biological assays
Stages in drug discovery
Stage 1: Target Identification
Stage 2: Target validation Stage 3: Lead identification
Stage 4: Lead optimization
Requirements to test in human volunteers
Preclinical technology
Pharmaceutics (Science of dosage form design)
Pharmacology/ Toxicology (The study of drug action)
Testing on Human volunteers
Phase I:•Designed to verify safety & tolerability of the candidate drug in humans •Typically takes 6-9 months
Phase II:•To determine effectiveness and further safety of the candidate drug in humans•Generally takes 6 months to 3 yrs
Phase III:•Expanded testing•Takes 1-4 yrs