Apr14_Rajnarayanan_PMY311 - Pharmacophore-based drug design...

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Pharmacophore-based drug design Determine the effects of structural changes on activity of drug: structure-activity relationships (SARs) 1. Data collection: Publications; patents; biological activity; NMR and X-ray data; physiochemical properties Determine identity of a “lead compound”: Screen natural and synthetic banks of compounds for activity Folk medicine Natural ligand Drug already known Computer-aided drug design Computerized search of structural databases
Pharmacophore: A specific 3D arrangement of chemical groups common to active molecules and essential to their biological activities Pharmacophore-based drug design This information will result in the identification of a pharmacophore… 2. Analysis: integrate information about drug (and target) to generate hypothesis about activity
Why make new lead compounds? Increase activity (make binding stronger) Decrease side effects (increase selectivity) Improve ease and efficiency of administration to patient Potentially find a better synthetic route Pharmacophore-based drug design Approach: Molecular mimicry . If you know the pharmacophore for your target, you can create new lead compounds based on the pharmacophore! 3. Design new structures.
Pharmacophore-Based Drug Design Simple example 1: 3D structures are known 1. Data collection: biological activity of lead compound (and other compounds) 2. Analysis: biologically active molecules share the same pharmacophoric features (superimpose 3D structures&find common features)
Pharmacophore-Based Drug Design Simple example 1: 3D structures are known 3. Design new structures. New molecular mimic will be tested.
Pharmacophore-Based Drug Design Example 2: (A more typical example) Biologically active conformations are not known. 1. Data collection: biological activity. Two molecules below show good activity. Data collection: Determination of biologically active conformation
Pharmacophore-Based Drug Design Example 2 (cont): If no 3D data are available, use computers! Bioactive conformations are not always the most stable conformations, but are within about 12kJ/mole or 3kcal/mole) Data collection: Determination of biologically active conformation
cyclohexane
Pharmacophore-Based Drug Design Generate low energy conformations for each active molecule: A: Etc… B: Etc… 2. Data analysis. Hypothesis : bioactive conformations share 3D features required for activity…Superimpose the generated conformations to define a pharmacophore Example 2 (cont): Data collection: Determination of biologically active conformation
Notes: More rigid molecules have fewer conformations easier to analyze Flexible molecules have many conformations often must examine conformationally restricted analogs to determine bioactive conformation. (Move from computer to lab: Chemical synthesis of analogs!) •Superimposing molecules: don’t look at sterics only think of physical properties of molecule.

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