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. 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. 2D descriptors
Descriptors calculated from the 2D structure
1. Simple counts:
-H-bond donors
-H-bond acceptors
-Ring systems
-Rotatable bonds
-Molecular weight
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. 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”
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. 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. 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. 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. 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. 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. 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. 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. 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
19. Stages in drug discovery
Stage 1: Target Identification
Stage 2: Target validation
Stage 3: Lead identification
Stage 4: Lead optimization
20. Requirements to test in human
volunteers
Preclinical technology
Pharmaceutics (Science of dosage form design)
Pharmacology/ Toxicology (The study of drug action)
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
