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 theirKey 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