Bio-targets -1 PDF

Module 2: Biological Targets and Their Modulation 1  Biological molecules are modular Protein – Linear chain of amino acids – Amide bonds Nucleic acids – Linear chain of nucleotides – Phosphate esters Polysaccharides – Linear...

Module 2: Biological Targets and Their Modulation 1  Biological molecules are modular Protein – Linear chain of amino acids – Amide bonds Nucleic acids – Linear chain of nucleotides – Phosphate esters Polysaccharides – Linear chains of sugars, some are branched – Acetals Lipids – Linear chains of acetate or propionate – Chain is modified so the assembly units are “hidden” – Reduced aldol (1,3-dicarbonyl) 2  Modular construction makes life possible Easily assemble complex structures using simple molecule components Easily disassemble complex structures and regenerate parts for reuse Only need 1 enzyme system for each biomolecule type and function – Proteins made by ribosome – Protein disassembled by proteasome 3 Biological Assembly 4 Biological Disassembly 5 Biological Reassembly 6 Drugs produce effects by binding to biomolecules Proteins are the most common target – Nucleic acids are less common Drugs produce effects by binding to biological molecules Drug Drug Biological response Biological Molecule Biological Molecule 7  Biomolecules have well-defined 3-D shapes They create three-dimensional chemical environments Drugs interact with biological molecules in 3-D way The shape and pattern of electron density determine binding – Non-covalent interactions Some drugs react chemically with biological molecules – Covalent bonds Drug Drug Biological response Biological Molecule Biological Molecule 8  Proteins are made of amino acids 20 different canonical types of amino acid are used – Occasionally, some proteins contain modified or unusual amino acids Amino acids share the same backbone and stereochemistry, but differ by their side chains (R) The chemical properties of side chains vary, contributing to the diverse functions of proteins 9 Amino acid side chain properties Non-polar Side Chains Alkyl Aliphatic Aromatic Alanine Phenylalanine Valine Tyrosine Leucine OH Isoleucine Tryptophan NH Methionine S 10 Amino acid side chain properties Acidic Side Chains Aspartic acid Asparagine CO 2H Glutamic acid CO 2H Basic Side Chains Lysine NH 2 NH Arginine N NH 2 H N Histidine NH 11  Peptides are linear chains of amino acids Proteins are long peptides folded into a particular shape O R2 H2N OH amino acids OH H2N R1 O O R2 H2N OH peptide N H R1 O peptide bond (amide) 12  Formation of peptide bonds Leaving Group O O R2 H2N H2 N OH OH X H 2N R1 R1 O O R2 H2N OH N H R1 O peptide bond (amide) 13 Nucleophilic substitution of carboxylates 14 Amide bond formation – base catalysis 15 Amide bond formation – acid catalysis 16  Primary structure of proteins Sequence of amino acids in a protein – (this is the only information specified by a gene) Amino acids are joined by peptide bonds (amide bonds) O R2 O H N N N H H R1 O R3 Ala-Leu-Phe-Met-Pro-Cys-Ser- 17  Primary structure is a list By convention, amino acids in a protein are listed in order from the N-terminus towards the C-terminus 18 Identify the correct structure based on the sequence below Ala-Leu-Phe-Met- 19  Secondary structure Regions of local order in the backbone chain Forms small-scale structures such as: – -helix – -sheet – Loop – Turn Represented in ribbon structures 20  Origin of secondary structure Conformational restrictions in amide bonds Conformational restrictions between amide and - carbon Interactions between amide bonds – Intermolecular forces acting in an intramolecular way – Same forces that control solubility Side chain interactions within a region of the chain 21 Amide bond has double-bond character C,O,N are sp2 22 s-Cis and s-trans conformations 23 Amide “prefers” s-trans conformation O O H H N N H N N H s-trans s-cis O O H H N N H N N H 24 Backbone C-C bonds prefer certain conformations 25  Side chain interactions Negative charges attract positive charges Hydrogen bonding between side chains and backbones Non-polar side chains interact with other non-polar chains – steric interactions The result of these chemical interactions is the folding of the amino acid chain to produce large-scale structures 26 -helix 27 Ribbon diagrams for -helix 28  -structures -strand Several strands can associate together to form Sheets (-sheet) Large sheets can curl around themselves, forming cylinders (-barrels) 29 -sheet can be parallel or antiparallel 30 Ribbon diagrams for -structures 31  Loops Areas with no defined secondary structure Represented by “spaghetti” on ribbon diagrams 32  Turns Several types May not be explicitly represented on ribbon diagrams Look for areas where the chain changes direction by a large amount 33 Ribbon structures and secondary structures 34  Tertiary structure Overall three-dimensional shape of a protein Result of interactions between non-adjacent regions – Amino acid side chains – Two secondary structures (two helices) Contains regions of order – Secondary structure Contains less ordered regions – Loops 35  Tertiary structure and attractive forces Attractions between secondary structures cause the secondary structures to fold back on themselves These are mostly non-bonding interactions There are occasional covalent bonds 36 Tertiary structure and attractive forces 37 Tertiary structure and non-bonding interactions 38 Tertiary structure and non-polar interactions 39 Van der Waals interactions are very important polar side chains on the outside of the protein H2O CO2 H2O H2O H2O H2O OH NH3 H2O Protein H2O H2O H2O H2O H2O H2O non-polar side chains on the inside of the protein 40 Dipole interactions and H-bonds stronger inside hydrophobic environment Non-polar environment critical to holding protein together electrostatic attraction is weaker in water dipoles and hydrogen bond attraction weaker in water H2O H2O CO2 H2O NH2 O NH2 H2O H2O OH O2CH H Protein O H2N NH2 electrostatic attraction O is strong in non polar environment dipoles and hydrogen bond attraction strong in non-polar environment 41 Polar interactions in non-polar environments NaCl 42 Ribbon structures show tertiary structure 43  Some proteins form quaternary structures Two or more proteins bind together Sub-units can be the same or different 44  Protein-protein interactions are very strong Lots of surface contact area Lots of chemical interactions Exclusion of water from space between Proteins stick together well Difficult to separate some proteins 45  Overall structure determines function Most of the molecule is a scaffold Only a small part is normally “functional” 46