Key to Problems for Drug Design Courses(ID) 1. The nature of the pathological target. It's the site of action, nature of desired action, stability, ease of absorption and distribution, metabolism, dosage form and regimen 2. See the preface of the textbook. The factors affecting the pharmacokinetic phase are absorption, distribution, metabolism and elimination. The factor affecting the pharmacodynamic phase is the ctronic structure of the 3. Deconvolution is a method, based on the process of elimination, of reducing the number of screening tests required to locate the most active member of a library consisting of a mixture of all the components. It is based on producing and biologically assaying similar secondary libraries that contain one less building block than the original library. It is emphasized that the biological assay is carried out on a mixture of all the members of the secondary library. If the secondary library is still as active as the original library, the missing building block is not a part of the active structure Repetition of this process will eventually result in a library that is inactive, which indicates that the missing building block in this library is part of the active structure. In order to be effective, decovolution procedures require that both the synthesis and assay of the library be rapid. The procedure is complicated when there is more than one active in the library 4. High-throughput screening(HTS)is the name given to rapid semi-automated simultaneous primary screening of large number of compounds, mixtures or extracts for active compounds. The process is based on the use of bioassays that are rapid to carry out and require very small quantities of the reagents and test compound. These assays are carried out on 96- and bigger -well plates using specialized handling equipment. They are based on the test compound interacting with a target, such as an enzyme, a cell membrane receptor, hormone, nuclear receptors and dNA that is related to the disease state under investigation (a) whole cell assays are preferred when the nature of the steps in the mechanism of the disease state have not been well defined. They also offer a number of other advantages over biochemical tests. For example, whole cell tests may identify compounds that act at sites other than the target site. And test compounds that are either too hydrophobic, and as a result bind too strongly to serum albumin, or will not cross cell membranes will not usually be active. Therefore it is relatively easy to identify these compounds that are toxic and often readily identified because of their effect on the cells used in the test (b) Hit rates are defined as the number of active samples discovered by an assay expressed as percent of the total samples used in that screen. Assays with values of about 0. 1-l percent hits are normally regarded as being valid. Inaccurate hit values may be obtained because of false positive (c)Low a run of inactive compounds. High: a run of active compounds, too low a criterion for a it; assay too general, resulting in it detecting active compounds with different types of activity 6. The reduction in pH reduces the negative charge of the albumin and so increases its electrophilic character. Therefore, as amphetamine molecules are nucleophilic in nature their
Key to Problems for Drug Design Courses (II) 1. The nature of the pathological target. It’s the site of action, nature of desired action, stability, ease of absorption and distribution, metabolism, dosage form and regimen. 2. See the preface of the textbook. The factors affecting the pharmacokinetic phase are absorption, distribution, metabolism and elimination. The factor affecting the pharmacodynamic phase is the stereoelectronic structure of the compound. 3. Deconvolution is a method, based on the process of elimination, of reducing the number of screening tests required to locate the most active member of a library consisting of a mixture of all the components. It is based on producing and biologically assaying similar secondary libraries that contain one less building block than the original library. It is emphasized that the biological assay is carried out on a mixture of all the members of the secondary library. If the secondary library is still as active as the original library, the missing building block is not a part of the active structure. Repetition of this process will eventually result in a library that is inactive, which indicates that the missing building block in this library is part of the active structure. In order to be effective, decovolution procedures require that both the synthesis and assay of the library be rapid. The procedure is complicated when there is more than one active in the library. 4. High-throughput screening (HTS) is the name given to rapid semi-automated simultaneous primary screening of large number of compounds, mixtures or extracts for active compounds. The process is based on the use of bioassays that are rapid to carry out and require very small quantities of the reagents and test compound. These assays are carried out on 96- and bigger-well plates using specialized handling equipment. They are based on the test compound interacting with a target, such as an enzyme, a cell membrane receptor, hormone, nuclear receptors and DNA, that is related to the disease state under investigation. 5. （a）Whole cell assays are preferred when the nature of the steps in the mechanism of the disease state have not been well defined. They also offer a number of other advantages over biochemical tests. For example, whole cell tests may identify compounds that act at sites other than the target site. And test compounds that are either too hydrophobic, and as a result bind too strongly to serum albumin, or will not cross cell membranes will not usually be active. Therefore it is relatively easy to identify these compounds that are toxic and often readily identified because of their effect on the cells used in the test. (b) Hit rates are defined as the number of active samples discovered by an assay expressed as a percent of the total samples used in that screen. Assays with values of about 0.1-1 percent hits are normally regarded as being valid. Inaccurate hit values may be obtained because of false positive and negatives. (c) Low: a run of inactive compounds. High: a run of active compounds; too low a criterion for a hit; assay too general, resulting in it detecting active compounds with different types of activity. 6. The reduction in pH reduces the negative charge of the albumin and so increases its electrophilic character. Therefore, as amphetamine molecules are nucleophilic in nature their
binding should improve with the decrease in pH. Part of this binding will involve salt formation between the amphetamine and the albumin. Amphetamine is more likely to form salts in which it acts as the positive ion as the electrophilic nature of the albumin increases 7. Replace the ester(lactone) with a less easily hydrolysed amide group. Introduce bulky ethyl or propyl groups on either side of the lactone group to reduce the ease of hydroysis. Use an enteric 8.(a) Yes, This structure only disagrees with one rule, namely the value of logP is too high(b) No, This structure does not comply with two rules, namely: too many hydrogen bond donors and too high a molecular mass. (c)Yes. This structure only disagrees with only rule, namely the value of logP is too high 9. Drugs act by binding to their target domains. This binding is only possible if their stereoelectronic structures are complementary to those of their target domains 10. Stereoisomers can exhibit different potencies, types of activity and unwanted side effects 11. A: (a)structurally rigid groups CHNC:CH CH3 H3C O、O N(CH2CH3)2 N CH3 (b)conformations H3C-. CH3 CH3 OCOCH3 H3C-N OCOCH 3C ④CH3 H2C④ H3C N CH3 COCh OCOCH3
binding should improve with the decrease in pH. Part of this binding will involve salt formation between the amphetamine and the albumin. Amphetamine is more likely to form salts in which it acts as the positive ion as the electrophilic nature of the albumin increases. 7. Replace the ester (lactone) with a less easily hydrolysed amide group. Introduce bulky ethyl or propyl groups on either side of the lactone group to reduce the ease of hydroysis. Use an enteric coating. 8. (a) Yes, This structure only disagrees with one rule, namely the value of logP is too high. (b) No, This structure does not comply with two rules, namely: too many hydrogen bond donors and too high a molecular mass. (c) Yes. This structure only disagrees with only rule, namely the value of logP is too high. 9. Drugs act by binding to their target domains. This binding is only possible if their stereoelectronic structures are complementary to those of their target domains. 10. Stereoisomers can exhibit different potencies, types of activity and unwanted side effects. 11. A: (a) structurally rigid groups CH N H C CH CH3 H3C O O H CH3 N CH3 CH3 H NH2 O N(CH2CH3 )2 O H3C O O H H N CH3 CH3 CH3 (b) conformations N H3C CH3 OCOCH3 N H3C CH3 OCOCH3 N OCOCH3 H2C N H3C H2C CH3 H3C CH3 OCOCH3 © configuration
OCOCH3 N(CH3)3 N(CH3)3 OCOCH3 H H3COCO H3)3 N(CH3)3 12. Drugs administrated orally as a solid or in suspension have to dissolve in the aqueous gastric fluid before they can be absorbed and transported via the systemic circulation to their site of action Either by absorption or by direct administration, the drugs's solubility will influence its ease of transport to the body compartments available to that drug 13.(a)Solutions whose properties are linearly proportional to the concentration of the solute are referred to as ideal solutions (b) Polar solute have permanent dipoles and so there are strong electrostatic attractive forces between their particles and the polar water molecules 14.(a)High polar group to carbon atom ratio b) The presence of polar groups that can form hydrogen bond to water molecules and ionize in 15.(a)Form salts that would improve water solubility but would break down to yield the drug in the biological system (b) Introduce water solubilising groups into a part of the structure that is not the pharmac ophone of the drug (c) Formulate as a suitable dosage forn 16. (a) Any method for carboxylic acid, phosphate and sulphonic acid group (b) Any method for basic groups (c) Any method for polyhydroxy and ether residues 17. Structure-activity relationships. These are the general relationships obtained from a study of the changes in the structure of a lead. These changes are used to find or predict the structure with the optimum activity
H H N(CH3 )3 H H OCOCH3 N(CH3 )3 H H OCOCH3 H H H H OCOCH3 H N(CH3 ) H 3 N(CH3 )3 H H H3COCO H H 12. Drugs administrated orally as a solid or in suspension have to dissolve in the aqueous gastric fluid before they can be absorbed and transported via the systemic circulation to their site of action. Either by absorption or by direct administration, the drugs’s solubility will influence its ease of transport to the body compartments available to that drug. 13. (a) Solutions whose properties are linearly proportional to the concentration of the solute are referred to as ideal solutions. (b) Polar solute have permanent dipoles and so there are strong electrostatic attractive forces between their particles and the polar water molecules. 14. (a) High polar group to carbon atom ratio (b) The presence of polar groups that can form hydrogen bond to water molecules and ionize in water. 15. (a) Form salts that would improve water solubility but would break down to yield the drug in the biological system. (b) Introduce water solubilising groups into a part of the structure that is not the pharmacophore of the drug. (c) Formulate as a suitable dosage form. 16. (a) Any method for carboxylic acid, phosphate and sulphonic acid groups. (b) Any method for basic groups. (c) Any method for polyhydroxy and ether residues. 17. Structure-activity relationships. These are the general relationships obtained from a study of the changes in the structure of a lead. These changes are used to find or predict the structure with the optimum activity
18. The most popular halogen substitutions are the less reactive aromatic flurorine and chlorine groups. Othe aliphatic C-halgen bonds are weaker and so more reactive (b)CF3. It is approximately the same size as a chlorine atom 9. Bioisostere: Analogues can also be formed by replacing an existing substituent in the structure of a lead by a new substituent group Pharmacophore: The important functional groups that are required for binding or activity, and their relative positions in space (a) Sulphonic acid groups do not usually have any effect on the biological activity but will increase the rate of excretion of an analogue (b)Methyl groups usually increases the lipophilicity of the compound and reduces its water solubility as shown by an increase in the value of the partition coefficient (c)Thiol are not usually introduced into leads in SAR studies because they are readily metabolized by oxidation 21. QSAR is an attempt to remove this element of luck from drug design by establishing mathematical relationship in the form of an equation between biological activity and measurable physicochemical parameters. These parameters are used to represent properties such as lipophilicity, shape and electron distribution, which are believed to have a major influence on the drugs activity. They are normally defined so that they are in the form of numbers derived from practical data that are thought to be related to the property that the parameters represents 22. A: Lipophilicity: P(Partition coefficients), I(Lipophilic substituent constants), D(Distribution Coefficient) Shape: Es(The Taft steric parameter)and MR(Molar refractivity) Electronic effects: o(The Hammett constant) 23. advantages: less computing time, very large molecules may be modeled and can be used to give information on the binding of ligands to the target site. Disadvantages: accuracy of the structure depends on selecting the correct force field and parameter values. Structures are normally determined at zero Kelvin so they will have different conformations at room and bod 24. Local minimum energy conformations are the nearest conformation of local minimum energy from the starting conformation Global minimum energy conformations are the lowest conformation of global minimum energy thus is one kind of local minimum energy Though the global is not necessary the active conformation, it is also considered as the active conformation since the active conformation is one certain minimum energy conformation. 25. Molecular dynamics: show the dynamic nature of molecules by simulating the natural motion of the atoms in a structure
18. The most popular halogen substitutions are the less reactive aromatic flurorine and chlorine groups. Othe aliphatic C-halgen bonds are weaker and so more reactive. (b) CF3. It is approximately the same size as a chlorine atom. 19. Bioisostere: Analogues can also be formed by replacing an existing substituent in the structure of a lead by a new substituent group. Pharmacophore: The important functional groups that are required for binding or activity, and their relative positions in space. 20. (a) Sulphonic acid groups do not usually have any effect on the biological activity but will increase the rate of excretion of an analogue. (b) Methyl groups usually increases the lipophilicity of the compound and reduces its water solubility as shown by an increase in the value of the partition coefficient. (c) Thiol are not usually introduced into leads in SAR studies because they are readily metabolized by oxidation. 21. QSAR is an attempt to remove this element of luck from drug design by establishing a mathematical relationship in the form of an equation between biological activity and measurable physicochemical parameters. These parameters are used to represent properties such as lipophilicity, shape and electron distribution, which are believed to have a major influence on the drug’s activity. They are normally defined so that they are in the form of numbers derived from practical data that are thought to be related to the property that the parameters represents. 22. A: Lipophilicity: P(Partition coefficients), π(Lipophilic substituent constants),D(Distribution Coefficient) Shape: Es (The Taft steric parameter) and MR (Molar refractivity) Electronic effects: σ(The Hammett constant) 23. advantages: less computing time, very large molecules may be modeled and can be used to give information on the binding of ligands to the target site. Disadvantages: accuracy of the structure depends on selecting the correct force field and parameter values. Structures are normally determined at zero Kelvin so they will have different conformations at room and body temperatures. 24. Local minimum energy conformations are the nearest conformation of local minimum energy from the starting conformation. Global minimum energy conformations are the lowest conformation of global minimum energy, thus is one kind of local minimum energy. Though the global is not necessary the active conformation, it is also considered as the active conformation since the active conformation is one certain minimum energy conformation. 25. Molecular dynamics: show the dynamic nature of molecules by simulating the natural motion of the atoms in a structure
Docking: Superimpose the three-dimensional structure of a potential drug(ligand)on its possible 26. (a) Quantum mechanical approach is based on the real ization that electrons and all material particles exhibit wave-like properties. This allows the well defined, parameter free, mathematics of wave motions to be applied to electrons, atomic and molecular structure (b)A: The basis of these calculation is the Schrodinger wave equation, which in its simplest form may be stated as y= Ey Where p is a mathematical function known as the state function or time-dependent wave function that defines the state(nature and properties) of a system. In molecular modeling terms e t presents the total potential and kinetic energy of all the particles(neclei and electrons) in the structure and H is the Hamiltonium operator acting on the wave function +. Operators are mathetical methods of converting one function into another function in order to find a solution or olutions to the original function. For example, differentiation is an operator that transforms an equation representing a function into its first derivatives 27. The pharmacophore of a biologically active ligand is the three-dimensional geometric positions of the groups(pharmacophoric centers)of the ligand that form a unique pattern recognizable by the receptor 28. Flexible molecules are better able to adjust to the bindings site. Compound B, as the ethane residue joining the benzene rings can form different conformers. The ethane residue joining the benzene rings has a ridged structure
Docking: Superimpose the three-dimensional structure of a potential drug (ligand) on its possible target site. 26. （a）Quantum mechanical approach is based on the realization that electrons and all material particles exhibit wave-like properties. This allows the well defined, parameter free, mathematics of wave motions to be applied to electrons, atomic and molecular structure. （b）A: The basis of these calculation is the Schrodinger wave equation, which in its simplest form may be stated as: H = E Where ψis a mathematical function known as the state function or time-dependent wave function that defines the state (nature and properties) of a system. In molecular modeling terms Eψ represents the total potential and kinetic energy of all the particles (neclei and electrons) in the structure and H is the Hamiltonium operator acting on the wave function ψ. Operators are mathetical methods of converting one function into another function in order to find a solution or solutions to the original function. For example, differentiation is an operator that transforms an equation representing a function into its first derivatives. 27. The pharmacophore of a biologically active ligand is the three-dimensional geometric positions of the groups (pharmacophoric centers) of the ligand that form a unique pattern recognizable by the receptor. 28. Flexible molecules are better able to adjust to the bindings site. Compound B, as the ethane residue joining the benzene rings can form different conformers. The ethane residue joining the benzene rings has a ridged structure