Molecular descriptors

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
 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 )
 2D descriptors
Descriptors calculated from the 2D structure

1. Simple counts:
-H-bond donors

-H-bond acceptors

-Ring systems

-Rotatable bonds

-Molecular weight
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 features of a molecule such as atoms, ring centroids
and planes

2.Pharmacophore Keys
 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”
Drug design
 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
QSAR
 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