Medicine- A chemistry perspective III

Protein Structure

Protein Structure : Bonding interactions with water

Importance of bonding interactions ??

Covalent, ionic, hydrogenbonding, and, finally, van der Waals

More possible opportunities for van der Waals and hydrogen bonding interactions

hydrophobic and van der Waal interactions to largely determine the three-dimensionalShape of the protein

An understanding of these interactions is crucial to the design of Effective drugs that will target these binding sites

Protein Structure : Covalent Disulfide bond

vasopressin

oxytocin

The only amino acid that can form a covalent disulphide bond is cysteine

Oxytocin is normally produced in the hypothalamus and stored in the posterior pituitary gland

This helps with birth, maternal bonding, and lactation

 neurohypophysial hormone found in most mammals

retain water in the body and to constrict blood vessels

Protein Structure : Enzyme active site

Protein Structure

38%

19% 19%

24 %

Protein Structure : Quaternary Structure

Only proteins that are made up of a number of protein subunits have quaternary structure.

Protein Structure : Summary

Translation and post translational modifications

The process by which a protein is synthesized in the cell is called translation

Translation and post translational modifications

Several proteins are cleaved into smaller proteins or peptides following translation.

Crystallographic structure of a fragment of human fibrinogen

An enkephalin is a pentapeptide involved in regulating nociception in the body

Genomics

Genomics is a discipline in genetics that applies recombinant DNA, DNA sequencing methods, and bioinformatics to sequence, assemble, and analyze the function and structure of genomes (the complete set of DNA within a single cell of an organism)

The total length of the human genome is over 3 billion base pairs.

The genome is organized into 22 paired chromosomes, the X chromosome (one in males, two in females) and, in males only, one Y chromosome, all being large linear DNA molecules contained within the cell nucleus

Protein-coding sequences represent the most widely studied and best understood component of the human genome.

Coding sequences (protein-coding genes)

After genomics and transcriptomics, proteomics is the next step in the study of biological systems

Proteomics

Proteomics is the large-scale study of proteins, particularly their structures and functions

Secondary, tertiary, and quaternary structures are formed to maximize favorable intramolecular and intermolecular bonds, and to minimize unfavorable interactions.

Amino acids with polar residues are favored on the outer surface of a protein because this allows hydrogen bonding interactions with water. Amino acids with non-polar residues are favored within the protein because this maximizes Vander Waals and hydrophobic interactions.

Many proteins undergo post-translational modifications.

Proteomics is the study of the structure and function of novel proteins discovered through genomics.

Summary

Protein : Drug targets

Structural Proteins

Transport proteins

Enzymes and receptorsMiscellaneous proteins and protein protein interactions

Structural Proteins : Microtubule

Structural proteins do not normally act as drug targets

Structural proteins are fibrous proteins. The most familiar of the fibrous proteins are probably the keratins, which form the protective covering of all land vertebrates: skin, fur, hair, wool, claws, nails, hooves, horns, scales, beaks and feathers.

However, the structural protein tubulin is an exception.

Microtubules are a component of the cytoskeleton, found throughout the cytoplasm. These tubular polymers of tubulin can grow as long as 50 micrometers and are highly dynamic

paclitaxel and the vinca alkaloids vincristine andvinblastine.

These microtubules have various roles within the cell, including the maintenance of shape, exocytosis , and release of neuro transmitters.

Microtubule : Structure

Immunomicrographs of HeLa cells with microtubules (green) and DNA (red) displaying hallmarks of a typical cell division process

Henrietta Lacks

Microtubule : Drug target

The structural proteins of viruses are important to the survival of the virus outside their host cell. Some of these proteins are proving to be interesting drug targets for the design of new antiviral agents

Transport proteins

Transport proteins are present in the cell membrane and act as the cells smugglers smuggling the importantchemical building blocks of amino acids, sugars, and nucleic acid bases across the cell membrane such thatthe cell can synthesize its proteins, carbohydrates, and nucleic acids. Also transmit neurotransmitters

why is this smuggling operation necessary?

Why Can these molecules pass through the membrane by themselves?

Why T-protein float within cell membrane ?

Are T-proteins identical ?

Several important drugs which target transport proteins

Drug Target : Enzymes and receptors

Enzymes are molecules that accelerate, or catalyze, chemical reactions

A receptor is a protein molecule usually found embedded within the plasma membrane surface of a cell that receives chemical signals from outside the cell. When such chemical signals bind to a receptor, they cause some form of cellular/tissue response, e.g. a change in the electrical activity of the cell

The most important drug targets in medicinal chemistry are enzymes and receptors

Miscellaneous proteins and protein protein interactions

The actions of insulin are mediated through a protein protein interaction

Summary

• Transport proteins, enzymes, and receptors are common drug targets.

• Transport proteins transport essential polar molecules across the hydrophobic cell membrane.

• Tubulin is a structural protein which is crucial to cell division and cell mobility.

• Many cell processes depend on the interactions of proteins with each other.