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Small molecules are used as inhibitors of protein action - as drugs. They most often do this by blocking the active site within the protein. Potential drugs can be screened computationally to determine if they are strongly bound to the protein. Figure 1 shows a possible conformation of a candidate drug molecule, 4-bromo-2- carboxymethylamide-pyrrole (abbreviation: BCMAP) at the active site of a protein (abbreviation: PR). Figure 2 shows the full protein structure whilst figure 3 shows a known inhibitor of the protein at the site, overlayed with another calculated conformer of BCMAP. (b) Outline how you would identify likely geometries of BCMAP in the binding site of PR. You need to consider different conformers of BCMAP but only the single active site in PR. Explain how you would rank the more probable geometries for comparison to experimental data on known inhibitors (such as in Figure 3). You should comment on any approximations to the protein structure that may be necessary or reasonable to make. Figure 1. 4-bromo-2-carboxymethylamide-pyrrole (BCMAP) (C, N, O, and Br atoms in yellow, blue, red, and brown, respectively) in the active site of the protein structure.

Small molecules are used as inhibitors of protein action - as drugs. They most often do this by blocking the active site within the protein. Potential drugs can be screened computationally to determine if they are strongly bound to the protein. Figure 1 shows a possible conformation of a candidate drug molecule, 4-bromo-2- carboxymethylamide-pyrrole (abbreviation: BCMAP) at the active site of a protein (abbreviation: PR). Figure 2 shows the full protein structure whilst figure 3 shows a known inhibitor of the protein at the site, overlayed with another calculated conformer of BCMAP. (b) Outline how you would identify likely geometries of BCMAP in the binding site of PR. You need to consider different conformers of BCMAP but only the single active site in PR. Explain how you would rank the more probable geometries for comparison to experimental data on known inhibitors (such as in Figure 3). You should comment on any approximations to the protein structure that may be necessary or reasonable to make. Figure 1. 4-bromo-2-carboxymethylamide-pyrrole (BCMAP) (C, N, O, and Br atoms in yellow, blue, red, and brown, respectively) in the active site of the protein structure.

Human Anatomy & Physiology (11th Edition)
Human Anatomy & Physiology (11th Edition)
11th Edition
ISBN:9780134580999
Author:Elaine N. Marieb, Katja N. Hoehn
Publisher:Elaine N. Marieb, Katja N. Hoehn
Chapter1: The Human Body: An Orientation
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Small molecules are used as inhibitors of protein action - as drugs. They most often do this by blocking the active site within the protein. Potential drugs can be screened computationally to determine if they are strongly bound to the protein. Figure 1 shows a possible conformation of a candidate drug molecule, 4-bromo-2- carboxymethylamide-pyrrole (abbreviation: BCMAP) at the active site of a protein (abbreviation: PR). Figure 2 shows the full protein structure whilst figure 3 shows a known inhibitor of the protein at the site, overlayed with another calculated conformer of BCMAP. (b) Outline how you would identify likely geometries of BCMAP in the binding site of PR. You need to consider different conformers of BCMAP but only the single active site in PR. Explain how you would rank the more probable geometries for comparison to experimental data on known inhibitors (such as in Figure 3). You should comment on any approximations to the protein structure that may be necessary or reasonable to make. Figure 1. 4-bromo-2-carboxymethylamide-pyrrole (BCMAP) (C, N, O, and Br atoms in yellow, blue, red, and brown, respectively) in the active site of the protein structure.
Transcribed Image Text:Small molecules are used as inhibitors of protein action - as drugs. They most often do this by blocking the active site within the protein. Potential drugs can be screened computationally to determine if they are strongly bound to the protein. Figure 1 shows a possible conformation of a candidate drug molecule, 4-bromo-2- carboxymethylamide-pyrrole (abbreviation: BCMAP) at the active site of a protein (abbreviation: PR). Figure 2 shows the full protein structure whilst figure 3 shows a known inhibitor of the protein at the site, overlayed with another calculated conformer of BCMAP. (b) Outline how you would identify likely geometries of BCMAP in the binding site of PR. You need to consider different conformers of BCMAP but only the single active site in PR. Explain how you would rank the more probable geometries for comparison to experimental data on known inhibitors (such as in Figure 3). You should comment on any approximations to the protein structure that may be necessary or reasonable to make. Figure 1. 4-bromo-2-carboxymethylamide-pyrrole (BCMAP) (C, N, O, and Br atoms in yellow, blue, red, and brown, respectively) in the active site of the protein structure.
Figure 2. Cartoon (ribbon) structure of the entire protein with a known inhibitor in position, as determined experimentally. Cations and water molecules in the protein structure are omitted for clarity. The links labelled can be cleaved chemically. lle1122 Cleavable Links Leul120 Tyr1167 Asn1168 Val1174 Prol110 Figure 3. An overlay of a known inhibitor (from Figure 2) and an example conformer of BCMAP. Dashed lines indicate hydrogens bonds and electrostatic interactions. The isolated cyan atoms are sodium cations and the isolated red atoms the determined positions of the oxygen in a water molecule.
Transcribed Image Text:Figure 2. Cartoon (ribbon) structure of the entire protein with a known inhibitor in position, as determined experimentally. Cations and water molecules in the protein structure are omitted for clarity. The links labelled can be cleaved chemically. lle1122 Cleavable Links Leul120 Tyr1167 Asn1168 Val1174 Prol110 Figure 3. An overlay of a known inhibitor (from Figure 2) and an example conformer of BCMAP. Dashed lines indicate hydrogens bonds and electrostatic interactions. The isolated cyan atoms are sodium cations and the isolated red atoms the determined positions of the oxygen in a water molecule.
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