Drug Design and Development

Module I- Dr. Jinny, AIB, AUH

• Module I: Drug targets classification
• DNA, RNA, post-translational, processing
enzymes, metabolic enzymes involved in nucleic
acid synthesis, G-protein coupled receptors
(monomeric transmembrane proteins), small
molecule receptors, neuropeptide receptors, ion
channels (monomeric multi-transmembrane)
proteins, ligand-gated ion channels (oligomeric
transmembrane proteins), transporters (multi-
transmembrane proteins).
DNA, RNA, post-translational, processing
enzymes, metabolic enzymes involved in
nucleic acid synthesis
• Nucleotides are the Building Blocks of the Nucleic Acids - DNA
and RNA
• Cells Make Nucleotides by Two Pathways - de novo and
Salvage Synthesis
• Purines are Made Separately from Pyrimidines, dNTPs are
Made from Ribonucleoside Diphosphates, Thymidine
Nucleotides are Made from Uridine Nucleotides
• Catabolism of Adenine Nucleotides
 Basics of Post Translation Modifications
• Translation is the synthesis of proteins from an mRNA template
• This process involves several key molecules: mRNA, Ribosome,
tRNA, Release Factor.
• It includes primarily three steps: initiation, elongation and
termination
• The peptide chain undergoes folding, addition of some amino acids,
carbohydrates can happen.
• Changes in the hydrogen bonding may result in changes in the
secondary and tertiary structures
• Some of the proteins may remain in cytosol while others are
transported across the membrane or even imported into cellular
organelles(mitochondria or choloroplast) to accomplish their
functions.
• It can be studies under different types- Trimming, Covalent
modification, Ubiquitination.
 Post Translation
• Protein post-translational modifications (PTMs) increase the
functional diversity of the proteome by the covalent addition of
functional groups or proteins, proteolytic cleavage of regulatory
subunits, or degradation of entire proteins.
• These modifications include phosphorylation, glycosylation,
ubiquitination, nitrosylation, methylation, acetylation, lipidation
and proteolysis and influence almost all aspects of normal cell
biology and pathogenesis.
• Therefore, identifying and understanding PTMs is critical in the
study of cell biology and disease treatment and prevention.
• PTMs occur at distinct amino acid side chains or peptide
linkages, and they are most often mediated by enzymatic
activity.
• These enzymes include kinases, phosphatases, transferases
and ligases, which add or remove functional groups, proteins,
lipids or sugars to or from amino acid side chains; and
proteases, which cleave peptide bonds to remove specific
sequences or regulatory subunits.
• Many proteins can also modify themselves using autocatalytic
domains, such as autokinase and autoproteolytic domains.
 Protein Translational Modification
• Protein PTMs can also be reversible depending on the nature of
the modification. For example, kinases phosphorylate proteins at
specific amino acid side chains, which is a common method of
catalytic activation or inactivation.
• Conversely, phosphatases hydrolyze the phosphate group to
remove it from the protein and reverse the biological activity.
• Proteolytic cleavage of peptide bonds is a thermodynamically
favorable reaction and therefore permanently removes peptide
sequences or regulatory domains.
 Small molecule receptors
• Cell surface receptors bind to their ligands (signaling molecules)
via their extracellular domains.
• In all cases, binding causes a conformational change in the
receptor that leads to the transmission of an intracellular signal.
• Binding specificity and affinity are determined by the extent of
molecular complementarity between the ligand and the receptor.
• A given receptor may exhibit specificity for a certain ligand or a
group of closely related (structurally) ligands.
• A given ligand may bind to a number of different types of
receptors, that exhibit different effectorspecificity (different cell
responses).
• Further, two receptors that bind different ligands, may signal via
the same intracellular signal transduction system, even within a
single cell
 G-protein coupled receptors
(monomeric transmembrane proteins)
 GPCRs
• These are invloved in the information transfer
(signal transduction) from outside the cell to
the cellular interior.
• GPCRs are responsible for every aspect of
human biology –vision, taste, smell,
sympathetic and parasympathetic nervous
functions, metabolism and immune regulation
to reproduction.
 Neuropeptide receptors
• Neuropeptides are small proteins present on cell surface used by
neurons to communicate to each other. NPY is short for Neuropeptide Y.
• Neuron signaling molecules once secreted do not get back into the cell
system unlike dopamine, serotonin.
• Tachykinin peptides are one of the largest families of neuropeptides,
found from amphibians to mammals.
• Neuropeptide Y receptors are a class of G-protein coupled
receptors which are activated by the closely related peptide
hormones neuropeptide Y, peptide YY (peptide tyrosine
tyrosine) and pancreatic polypeptide. These receptors are involved in
the control of a diverse set of behavioral processes
including appetite, circadian rhythm, and anxiety.
• Activated neuropeptide receptors release the Gi subunit from
the heterotrimeric G protein complex. The Gi subunit in turn inhibits the
production of the second messenger cAMP from ATP.
Ion channels (monomeric multi-
transmembrane) proteins
ligand-gated ion channels (oligomeric
transmembrane proteins)
Transporters (multi-transmembrane
proteins)