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Molecular descriptors
Molecular descriptors
Numerical values that characterize properties of molecules
They may represent
• The physicochemical ...
Molecular descriptors
They vary in the complexity of the information they encode
and in the time required to calculate the...
2D descriptors
Descriptors calculated from the 2D structure
1. Simple counts:
-H-bond donors
-H-bond acceptors
-Ring syste...
2. Physico-chemical properties
- Hydrophobicity (logP)
3. Molar refractivity
4. Topological indices
3D descriptors
1.3D fragment screens
These encode spatial relationships (e.g. distances & angles) between
the different fe...
Drug
In pharmacology,
“A chemical substance used in the treatment, cure, prevention,
or diagnosis of disease or used to ot...
Drug design
How can drugs be designed?
Traditional approach: Screening approach
• Trial and error as molecular mechanisms of disease
n...
Molecular basis of Drug specificity
Molecular specificity involves
• Binding of drug to target with suitable affinity
(Hig...
Proteins as Targets of drugs
Proteins are the cellular targets of many drugs.
Proteins can be
• Cytosolic
• Membrane bound...
Rational drug design
Application of biocomputing in drug design/discovery
• Optimize the pharmacological profile of existi...
Structure-based drug design
3D structure of a drug target interacting with small molecules is
used to guide drug discovery...
Combinatorial Chemistry
Strategy: Make a lot of molecules with combinatorial
chemistry and devise rapid tests for utility
...
Ligand-based drug design
Pharmacophore: A set of structural features in a molecule
that is recognized at a receptor site a...
Best strategy
Structure-based drug design coupled with combinatorial
techniques
• Use structure to design basic skeleton
•...
QSAR
Quantitative structure-activity relationships (QSAR)
Represent an attempts to correlate structural or property
descri...
QSAR
Stages in drug discovery
Stage 1: Target Identification
Stage 2: Target validation
Stage 3: Lead identification
Stage 4: L...
Requirements to test in human
volunteers
Preclinical technology
Pharmaceutics (Science of dosage form design)
Pharmacology...
Testing on Human volunteers
Phase I:
•Designed to verify safety & tolerability of the candidate drug in
humans
•Typically ...
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Drug design

  1. 1. Molecular descriptors
  2. 2. Molecular descriptors Numerical 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
  3. 3. Molecular descriptors They 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 )
  4. 4. 2D descriptors Descriptors calculated from the 2D structure 1. Simple counts: -H-bond donors -H-bond acceptors -Ring systems -Rotatable bonds -Molecular weight
  5. 5. 2. Physico-chemical properties - Hydrophobicity (logP) 3. Molar refractivity 4. Topological indices
  6. 6. 3D descriptors 1.3D fragment screens These encode spatial relationships (e.g. distances & angles) between the different features of a molecule such as atoms, ring centroids and planes 2.Pharmacophore Keys
  7. 7. Drug In pharmacology, “A chemical substance used in the treatment, cure, prevention, or diagnosis of disease or used to otherwise enhance physical or mental well-being”
  8. 8. Drug design
  9. 9. 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
  10. 10. 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
  11. 11. 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
  12. 12. 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
  13. 13. 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
  14. 14. 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
  15. 15. 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
  16. 16. 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
  17. 17. 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
  18. 18. QSAR
  19. 19. Stages in drug discovery Stage 1: Target Identification Stage 2: Target validation Stage 3: Lead identification Stage 4: Lead optimization
  20. 20. Requirements to test in human volunteers Preclinical technology Pharmaceutics (Science of dosage form design) Pharmacology/ Toxicology (The study of drug action)
  21. 21. 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
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Drug design

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