Medicinal Chemistry: An Overview

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1 Medicinal Chemistry: An verview Lecture Date Topic Course utline 20/2/7 General Aspects of Medicinal Chemistry 2 206/0/07 General Biochemistry 206/0/2 Principles of Chemical Synthesis 4 206/02/04 Chemical Synthesis of Small and Complex Molecules 206/02/8 Chemical Synthesis of Peptides 6 206/0/0 Strategies for Discovery of Lead Compounds 7 206/0/7 Structure Activity Relationship 8 206/0/ Spatial rganization, Receptor Mapping and Molecular Modeling 9 206/04/4 Pharmacokinetic Properties 0 206/04/28 Legal and Economic Aspects of Drug Development

2 Biochemistry The chemical study of the various processes occurring in living things. hierarchical organization of biological structures 2

3 Molecules of Life Proteins: composed of amino acid building blocks. ucleic acids: composed of nucleotides. Carbohydrates: composed of sugars. Lipids: composed of organic compounds that are essentially insoluble in water due to mainly hydrophobic nature. Vitamins: organic compounds required in small amounts by the body. ormones: intercellular chemical messengers.

Acid-Base Theory A + 2 + + A BrØnsted acid BrØnsted base conjugate acid conjugate base A + + A (proton) dissociation constant (K) K = [ + ] [A ] [A] for strong acids, K > for weak acids, K < The

4 Acid-Base Theory A A BrØnsted acid BrØnsted base conjugate acid conjugate base A + + A (proton) dissociation constant (K) K = [ + ] [A ] [A] for strong acids, K > for weak acids, K < The relative concentrations of acids and bases determines the p of a solution p = pk + log [A ] [A] p for easy comparison of [ + ] p =!log[ + ] enderson!asselbalch equation The p of a solution is stabilized by a buffer Properties of an ideal buffer. Impermeability to biological membrane. 2. Biological stability and lack of interference with metabolic biological processes.. Lack of significant absorption of ultraviolet and visible light. 4. Lack of formation of insoluble complexes with cations.. Minimal effect of ionic composition or salt concentration. 6. Limited p change in response to temperature. 4

5 Laws of Thermodynamics First Law: Energy is conserved. ΔU = q w where ΔU = net energy q = heat w = work Second Law: The universe tends toward maximum disorder. S = k B InW where S = entropy k B = Boltzmann constant W = disorder Gibbs Free Energy: An indicator of spontaneity of constant temperature (T) and pressure processes. G = TS ΔG = Δ T ΔS where G = Gibbs free energy = Enthalpy when ΔG 0, process is spontaneous (exergonic). when ΔG 0, process is not spontaneous (endergonic).

6 Standard Amino Acids 2! C C General form R R = side chain with nonpolar side chains Zwitterionic form in the physiological p range C C R R R with polar side chains with charge polar side chains Glycine Gly G C C C S Methionine Met M C Alanine Ala A Isoleucine Ile I Phenylalanine Phe F C C Valine C Val V Leucine C Leu L 2 Proline Pro P Tryptophan Trp W 2 S Serine Ser S Cysteine Cys C Asparagine Asn 2 C Threonine Thr T Glutamine Glu Q Tyrosine Tyr Y 2 Lysine Lys K 2 Glutamic acid Glu E istidine is Arginine Arg R Aspartic acid Asp D onstandard amino acids also exist ydroxyproline -ydroxylysine 6

7 Peptide (Amide) Bond peptide bond indicated by green line C L-Ala + L-Ser 2 C Ala-Ser (a dipeptide) 2 2 C C C C C Angiotensin II (a linear octapeptide) C C C Wu et al. Journal of atural Products 20, 76, 694!70 C C ocardiamide B (a cyclic hexapeptide) 7

8 Protein Structure Primary structure amino acid sequence of its polypeptide chain. Secondary structure local spatial arrangement of polypeptide backbone (α helices and β sheets). Tertiary structure -D structure of polypeptide chain. Quaternary structure spatial arrangement of its subunits. Protein structures are determined by X-ray crystallography and nuclear magnetic resonance (MR). 8

9 Primary Structure S -terminus S C C-terminus -letter code: Met-Ser-Val-Tyr-Lys-Cys-Gly -letter code: M-S-V-Y-L-C-G = MSVYLCG 9

10 Secondary Structure (α-elix) Stereo, space-filling representation of an α-helical segment of sperm whale myoglobin (E-helix) PDB A6M 0

11 Secondary Structure (β-sheets) Anti-parallel

12 Topology of β-sheets airpin connection Right-handed crossover connection Left-handed crossover connection 2

13 Tertiary Structure The first protein X-ray structure was that of sperm whale myoglobin about 60 years ago. PDB MB PDB MB

14 " Quarternary Structure emoglobin contains α (yellow), α 2 (green), β (blue), and β 2 (cyan). The heme groups are in red. PDB 2DB 4

15 Solid Phase Peptide Synthesis M = first amino acid from the C-terminus S = protecting group for the side chain of M X = leaving group Y = main chain protecting group M 2 = second amino acid from the C-terminus Liberty Blue SPPS machine from CEM

16 Polysaccharides C C 2 L-Glucose C C 2 D-Glucose more stable 2!-D-Glucopyranose 4 less stable Cellulose is formed by!("4) gycosidic linkages between D-glucose residues n n #-Amylose is formed by #("4)-gycosidic bonds between D-glucose residues

Polysaccharides 4 6 2 Cellulose is formed by!

17 Polysaccharides Cellulose is formed by!("4) gycosidic linkages between D-glucose residues n n #-Amylose is formed by #("4)-gycosidic bonds between D-glucose residues

18 Lipids Triacylglycerols: nonpolar, C 8 water-insoluble, energy reservoirs. 0 -Palmitoleoyl-2-linoleoyl--stearoylglycerol C C 8 Glycerophospholipids: nonpolar hydrocarbon tail and polar phosphoryl-x head -amphiphilic molecules that are found in biological membranes. X is usually a polar alcohol X R P 2 R 2 8

19 Lipids A sphingomyelin: found in myelin sheath that surround nerve cell axons. C P C fatty acid residue Cholesterol: ) constitutes between 0 to 40% of the animal plasma membrane. 2) greater rigidity than other membrane lipids due to fused ring system. C C C phosphocholine head group C C C C C 9

20 Plasma Membrane 20

21 Fluid Mosaic Model Model was proposed by S. J. Singer and G. icolson. Science 972, 7, Experimental proof by M. Edidin. Journal of Cell Science 970, 7, 9. 2

22 DA 2 ' end A 4' ' ' ' C 2' T P 2 C P G P 2 ' P - ' end 22

23 Phosphoramidite method DA Synthesis Photolithographic method 2

24 DA Microarrays 24

25 Protein Folding The primary structure of a protein determines its threedimensional structure. elices and sheets fill space efficiently hence they form about 60% of the average protein. Internal residues mainly dictate protein folding. Some proteins are natively unfolded but fold on binding to their target protein. Proteins fold rapidly in an organized manner. Accessory proteins such as protein disulfide isomerases (PDI), peptidyl propyl cis-trans isomerases and molecular chaperones aid protein folding. 2

26 Protein Dynamics Atomic fluctuations bond vibrations between 0.00 and 0. nanometers that range from 0 and 0 seconds. Collective motions movement of side chains and entire domains between 0.00 and more than 0. nanometers that range from 0 2 and 0 seconds. Triggered conformational changes external stimulus induced movement of individual side chains and subdomains between 0.0 and greater than nanometers that range from 0 9 and 0 seconds. 26

27 Enzyme-Substrate Complex 27

Allosteric effector d b Allosteric inhibitor y or e Active

effector ovel binding site Allosteric site e Allosteric

Allosteric wn site to of Goodey & Benkovic ature Chemical

28 avior. of of eric tive site e site ally ric Allosteric Regulation a Allosteric effector d b Allosteric inhibitor y or e Active site Allosteric site c Allosteric activator Allosteric effector ovel binding site Allosteric site e Allosteric effector site of Active site Allosteric reat site d can Allosteric wn site to of Goodey & Benkovic ature Chemical Biology 2008,, cause the activity of the enzyme is indirectly under allosteric control via the bound protein with an allosteric

29 Enzyme Kinetics E + S k k! ES k 2 P + E E (enzyme), S (substrate), ES (enzyme-substrate), P (product), k (forward rate constant), k! (reverse rate constant) Michaelis-Menten equation! o = V max [S] K M + [S]! o (initial velocity) V max ( maximum velocity) [S] (substrate concentration) K M (Michaelis constant) 29

30 Transition State Theory transition state 0

31 Enzyme Inhibition Competive Inhibition 2 C succinate C 2 2 C C 2 malonate succinate dehydrogenase succinate dehydrogenase 2 C fumarate no reaction C 2 E + S + I EI + S k k 2 ES P + E k! no reaction E (enzyme), S (substrate), I (inhibitor), ES (enzyme-substrate), P (product), k and k 2 (forward rate constants) k! (reverse rate constant), EI (enzyme-inhibitor), ESI (enzyme-substrate-inhibitor), E + S Uncompetive Inhibition k k! ES + I k 2 P + E Mixed or oncompetive Inhibition E + S + I k k! ES + I k 2 P + E ESI no reaction EI ESI no reaction

32 Group-Transfer Reactions (transfer of phosphoryl, acyl and glycosyl groups) Y + P Y P X X Biochemical Reactions trigonal bipyramid intermediate Y P + X Reduction-oxidation (Redox) Reactions 2 2 P P 2 reduction oxidation P P 2 icotinamide adenine dinucleotide (oxidized form) (AD + ) icotinamide adenine dinucleotide (reduced form) (AD) Elimination Reactions R! R 2 R R! Isomerization Reactions R aldose R ketose Rearrangement Reactions methylmalonyl- * S CoA CoA mutase CoA S * C 2 C

33 Catalytic Mechanisms of Enzymes Acid-Base catalysis 4 6 A!-D-Glucose 2 4 A linear form 6 2 B 4 A "-D-Glucose 6 2 B B Covalent catalysis amine R 2 R R R R 2 C acetoacetate C C C C C C C acetone R 2

34 Catalytic Mechanisms of Enzymes Metal Ion catalysis Metalloenzymes contain tightly bound metal ions such as Fe 2+, Fe +, Cu 2+, Zn 2+, Mn 2+, or Co 2+. Metal-activated enzymes loosely bind metal ions such as a +, K + Mg 2+, or Ca 2+.. Proper orientation of substrates for reaction. 2. Mediate oxidation-redox reactions through reversible changes in oxidation states of the metal ion.. Stabilize or shield negative charge. Electrostatic catalysis supportive evidence indicate that charge distributions about active sites of enzymes stabilize transition states of the catalyzed reactions. rientation and proximity effects catalysis closeness of reacting centers has little effect on catalysis, they have to be properly oriented. Catalysis by selective transition state binding binding of the transition state of an enzyme-catalyzed reaction in preference to the substrate is an important rate enhancement mechanism. 4

35 Summary Life processes are regulated by biomolecules whose chemical structures determine their functions. A comprehensive understanding of the structures of these biomolecules is vital to clarifying various biomedical processes. ext Lecture, 206/0/2 Principles of chemical synthesis: the logic behind the magic of how molecules are assembly by organic chemists.

Chemistry Chapter 22

Chemistry Chapter 22 hemistry 2100 hapter 22 Proteins Proteins serve many functions, including the following. 1. Structure: ollagen and keratin are the chief constituents of skin, bone, hair, and nails. 2. atalysts: Virtually