An Introduction to Medicinal Chemistry PDF

# An Introduction to Medicinal Chemistry ## Chapter 3 Drug targets proteins Salih Al-Jabour, Dr.rar.nat Pharmacy Department AlQuds University Jerusalem, Palesinte ### 1. The building blocks for proteins - Proteins are macromolecules made up of amino acid building blocks - There are 20 common ami...

# An Introduction to Medicinal Chemistry ## Chapter 3 Drug targets proteins Salih Al-Jabour, Dr.rar.nat Pharmacy Department AlQuds University Jerusalem, Palesinte ### 1. The building blocks for proteins - Proteins are macromolecules made up of amino acid building blocks - There are 20 common amino acids in human proteins ### 2. Zwitterions: Formerly called a dipolar ion, is a molecule with two or more functional group, of which at least one has a positive and one has a negative electrical charge and the net charge of the entire molecule is zero | | | | |---|---|---| | Cation | Zwitterion | Anion | | + NH3 | + NH3 | NH2 | | R-C-COOH | R-C-COO | R-C-COO | | H | H | H | | low pH | pH | high pH | ### 3. Amino acids - nonzwitterions - Non-ionized form of amino acids - Zwitterions - Ionized form of amino acids (zwitterion) ### 4. Amino acids are chiral molecules (except glycine, R=H) - Chiral Center - COOH (Carboxyl Group) - H (Amino Group) - R (Side Chain) - Mirror Image → Nonsuperimposable mirror images - Enantiomers → Isomers L (R), D(S). - General Amino Acid Features - Chirality and the R, S system - H<C<N<O - R - clockwise. - S- counterclockwise. - FISCHER DIAGRAM - COOH - H - C - R - H - NH2 - L-amino acid - R- isomoer (L) - D-amino acid - S- isomer (d) - Each amino acid has an identical head group. - Amino acids are chiral molecules (except glycine, R=H) - Only L-amino acids are present in human biochemistry - The L-amino acids are R-enantiomers (except cysteine; R= CH2SH) - Codes for amino acids | NAME | 3 LETTER CODE | ONE LETTER CODE | | -------- |:------------:|:------------:| | Alanine | Ala | A | | Arginine | Arg | R | | Asparagine| Asn | N | | Aspartic Acid| Asp | D | | Cysteine | Cys | C | | Glutamic Acid| Glu | E | | Glutamine | Gln | Q | | Glycine | Gly | G | | Proline | Pro | P | | Serine | Ser | S | | Tyrosine | Tyr | Y | | Histidine | His | H | | Isoleucine | Ile | I | | Leucine | Leu | L | | Lysine | Lys | K | | Methionine | Met | M | | Phenyalanine | Phe | F | | Threonine | Thr | T | | Tryptophan| Trp | W | | Valine | Val | V | - A GUIDE TO THE TWENTY COMMON AMINO ACIDS - Amino acids are the building blocks of proteins in living organisms. There are over 500 amino acids found in nature. However, the human genetic code only directly encodes 20. “Essential” amino acids must be obtained from the diet. While non-essential amino acids can be synthesized in the body. - Chart Key: - Aliphatic - Aromatic - Acidic - Basic - Hydroxylic - Sulfur containing - Amidic - Non Essential - Essential - Chemical Structure - single letter - three letter code - DNA codons - Alanine (Ala) - Glycine (Gly) - Isoleucine (Ile) - Leucine (Leu) - Proline (Pro) - Valine (Val) - Phenylalanine (Phe) - Tryptophan (Trp) - Tyrosine (Tyr) - Aspartic Acid (Asp) - Glumatic Acid (Glu) - Arginine (Arg) - Histidine (His) - Lysine (Lys) - Serine (Ser) - Threonine (Thr) - Cysteine (Cys) - Methionine (Met) - Asparagine (Asn) - Glutamine (Gln) ## 5. Willie Taylor’s scheme - Hydrophobic - Glycine (Gly.G) - Alanine (Ala.A) - Proline (Pro.P) - Valine (Val.V) - Leucine (Leu.L) - Isoleucine (Ile.I) - Tryptophan (Trp,W) - Phenylalanine (Phe,F) - Methionine (Met,M) - Polar - Serine (Ser.S) - Threonine (Thr,T) - Cysteine (Cys.C) - Charged (-) - Glutamine (Gln,Q) - Asparagine (Asn,N) - Glutamic Acid (Glu,E) - Aspartic Acid (Asp.D) - Charged (+) - Histidine (His,H) - Lysine (Lys,K) - Arginine (Arg.R) ## 6. Ketogenic Amino Acids - PITT = Ketogenic - Phenylalanine - Isoleucine - Threonine - Tryptophan - Tyrosine - Leucine - Lysine - Alanine - Glycine - Cysteine - Serine - Threonine - Tryptophan - Both Glucogenic and Ketogenic - Aspartate - Asparagine - Arginine - Proline - Histidine - Glutamine - Threonine - Methionine - Isoleucine - Valine ## 7. The Primary Structure of Proteins - Amino Acid (1) - H - N - H - H - C - R - C - O - O - H - Amino Acid (2) - H - N - H - H - C - R - C - O - O - H - N-terminus - C-terminus - Peptide bond - H - N - H - H - C - R - C - O - H - C - R - Dipeptide - Water ## 8. The Secondary Structure of Proteins - 1.24 A - 1.46 A - 1.53 A - C - CA - CA - Amino Terminus - N - H - Φψ - C - C - N - Φψ - Φψ - Carboxyl - Terminus - Phi torsion - Psi torsion - 3D Ramachadron Plot - A= Antiparallel beta sheet - P= parallel beta sheet - T= Right-hand twisted parallel and antiparallel beta sheet - alpha= Right-hand alpha helix L= left-hand alpha helix (rare) - Hydrogen bonding between peptide bonds - Position of side chains - Anti-parallel - parallel beta sheet ## 9. The Tertiary structure of proteins - Salih al-Jabour, Dr.rar.nat - Repulsive Interactions - Van Der Waals Interactions - Hydrogen Bonding Interactions - Ionic Bonding Interactions - Overall shape of the protein - Maximized favorable interactions and minimizes repulsive interactions. - Covalent bonds - disulphide links - SH HS - Cys Cys - S S - Cys Cys - Covalent bond - lonic or electrostatic bonds (salt bridges) - Asp - CO2 - lonic bond (salt bridge) - H3N-(CH2)4 - Lys - Hydrogen bonds - Ser - H-bond - Ser - H-O - Asp - Θ - H-bond - Ser - H-O - Van Der Waals interactions - Leu - H3C - CH3 H3C - Val - CH3 - van Der Waals interactions - Peptide chain - H-bond - Ser - CH2 - Phe - H-O-H - CH2CO2H-O - Asp - H-bond - Folding - H-O-C - Protein - Hydrophobic center - Me - Me - OH - H - O-H ## 10. The quaternary structure of proteins - Arrangement of proteins subunits with respect to each other. - Van Der Waals interactions - Hydrophobic regions ## 11. Protein Function - Structural proteins - tubulin - Tubulin polymerization - a-tubulin - Spontanaeous binding - tubulin heterodimer. - mRNA - DNA - B-tubulin - regulated assembly - Microtubule - regulated assembly - protofilament - Centromere - Tubulin depolymerization - Transport proteins - Transport polar molecules across the hydrophobic cell membrane - Polar molecules transported include amino acids and neurotransmitters - Extracellular space - Protein channel - Cell membrane - Carrier proteins - Intracellular space ## 12. Binding of the zn2+ ion to ferric uptake regulation protein from E. coli and the competition with Fe2+ binding - J Comput Aided Mol Des (2009) 23:199-208 - 10.1007/s10822-008-9251-2 - Salih Jabour - Mazen Y. Hamed - Received: 9 July 2008/Accepted: 3 November 2008/Published online: 21 November 2008 - Springer Science + Business Media B.V. 2008 - Journal of Molecular Graphics and Modelling 25 (2006) 234-246 - Available online at www.sciencedirect.com - Journal of Molecular Graphics and Modelling - www.elsevier.com/locate/JMGMD - Iron (II) triggered conformational changes in Escherichia coli fur upon DNA binding: a study using molecular modeling. - Mazen Y. Hamed, Salih Al-jabour - Computational Science program, Chemistry Department, Birzeit University, PO Box 14, Birzeit, Palestine - Received 21 September 2005; received in revised form 19 December 2005; accepted 20 December 2005 - Available online 27 January 2006 - Modeling study of the effect on DNA binding and conformation changes of Fur. - Lys45 - Cys92 - Asp105 - Lys76 - Lys45 - Lys76 - A la 130 - Cys92 - Asp 105 - Hsis 71 - Be 50 - Asp13 - Gly97 - Ala 109 - Asn 72