Molecular descriptors

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

2. Physico-chemical properties - Hydrophobicity (logP)

3. Molar refractivity

4. Topological indices

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”

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