Drug Design Lecture Notes PDF

# Drug Design and Mechanism of Action ## ⑤ Removal of susceptible metabolic group - **Tolbutamide**: - Has a benzylic carbon susceptible to metabolism. - After 6h, only 40ng/ml remains. - **Chloropropamide**: - Has a benzene ring susceptible to metabolism. - After 6h, only 1400ng/ml rema...

# Drug Design and Mechanism of Action ## ⑤ Removal of susceptible metabolic group - **Tolbutamide**: - Has a benzylic carbon susceptible to metabolism. - After 6h, only 40ng/ml remains. - **Chloropropamide**: - Has a benzene ring susceptible to metabolism. - After 6h, only 1400ng/ml remains. - In both cases, metabolism occurs at multiple sites, leading to a decrease in drug concentration. - Replacing these susceptible groups can reduce metabolism. - **Methoxyamine**: - Can be used to replace the susceptible group on tolbutamide. - The concentration of tolbutamide after 6h is 1400ng/ml. However, the remaining group is still susceptible to metabolism. - **Replacement of both susceptible groups**: - After 6h, the concentration of the drug is 6500ng/ml. - This indicates a successful removal of susceptible groups, leading to a higher drug concentration. - **Pyridine**: - Is a stable functional group that is resistant to metabolism. - Can be used to replace susceptible groups to increase drug stability. - **Allylic carbon**: - A carbon atom adjacent to a double bond, susceptible to metabolism. - **Acetylene group**: - A triple bond, resistant to metabolism. - **Fluoro**: - An atom that is highly resistant to metabolism. - **High metabolic stable**: - A drug that is resistant to metabolism due to the absence of susceptible groups. ## ⑥ Group Shifts - **Catechol**: - Susceptible to metabolism by COMT. - Can be converted to Resorcinol to prevent its metabolism. - **Resorcinol**: - More stable than catechol due to the group shift of the hydroxyl group. - This makes the drug resistance to metabolism by COMT. ## ⑦ Isosteric atoms or polar functional group - Isosteres: - Atoms or groups with similar electronic and geometric properties. - Can be used to replace susceptible groups to increase drug stability. - **(CH = N = 7)**: - Is an isosteric atom of a fluorine atom. - Can be used to replace a fluorine atom in a drug, which can increase drug stability by reducing metabolic susceptibility. ## ⑧ Apply Prodrug approach - **Prodrug**: - An inactive form of a drug that is converted into the active form in the body. - Can be used to increase drug stability or to improve drug delivery. - **Hydroxy group**: - Can be esterified to create a prodrug. - **Glucuronidation**: - A metabolic process that converts a hydroxy group into a glucuronide, which is more polar and water-soluble. - Glucuronidation can help to protect the drug from metabolism and improve its excretion. - **Propanolol**: - A drug that can be converted into a prodrug by esterification of its hydroxyl group. - The ester prodrug of propanolol is more stable and is readily absorbed by the body. ## Drug design – Lipinski Rule - The Lipinski Rule is a set of guidelines used to predict whether a drug is likely to be orally active. - This can be used to predict whether a drug will be a **Proper Kinetic** (easily absorbed orally) or **Deviate Kinetic** (not easily absorbed orally). - The 5 main Lipinski parameters include: - **Molecular weight**: <500 - **LogP**: <5 - **H-bond donar**: <5 - **H-bond acceptor**: >10 - **Rotatable bond**: <10 - The Lipinski rule also considers the flexibility of the drug molecule. ## Pharmaco dynamics - This refers to the mechanism of action of a drug. - There are two main mechanisms of action: - **Simple mechanism:** 0.5% of drugs - **Complicated mechanism:** The most common ### Simple mechanism - Depends on the physical characteristics of the drug. - For example, the neutralization of acids (basic salt) or the stimulation of smooth muscle (paralysis & constipation). ### Complicated mechanism - **Receptor-mediated** - the most common. - The drug interacts with a **receptor** to produce a physiological response. - **Receptors** are chemically reactive sites on the surface of cells or in the cell membrane. - The interaction between the drug and the receptor can result in a change in the shape of the receptor, which can lead to a cascade of events that ultimately produce the desired effect. ### Different types of interactions - **Agonist**: - A drug that binds to a receptor and activates it. - Agonists produce an effect similar to the effect produced by the natural ligand (the substance that normally binds to the receptor). - **Antagonist**: - A drug that binds to a receptor but does not activate it. - Antagonists block the effect of agonists. - **Partial agonists**: - A drug that binds to a receptor and activates it, but with less potency than a full agonist. - **Inverse agonists**: - A drug that binds to a receptor and reduces the activity of the receptor below its baseline level. ## Rate Theory - The rate theory explains how drugs bind to receptors and how they affect the physiological response. - The theory states that a receptor can exist in two conformations: - **Inactive conformation (RI)** - **Active conformation (RA)** - The rate at which a drug binds to the receptor (RI - RRA) determines the drug's effect. - For an agonist, the rate of binding to the receptor site is greater than the rate of dissociation. - So: - **If the rate of binding to RI is greater than the rate of dissociation, the drug will have a greater effect.** - **If the rate of dissociation is greater than the rate of binding, the drug will have a weaker effect.** ### Types of antagonists - **Competitive antagonists**: - Bind to the same site as the agonist, but do not activate the receptor. - They compete with the agonist for the same binding site. - These antagonists are usually **reversible**. - **Non-competitive antagonists**: - Bind to a different site on the receptor, and this binding changes the shape of the receptor. - **Allosteric antagonists**: - Bind to a site on the receptor that is different from the active site. - They do not directly interfere with the binding of the agonist, they change the receptor conformation making it less likely for the agonist to bind. ### Examples of rate theory in action - **Diclofenac**: Is more potent because it has a higher rate of binding to the receptor. - **Ibuprofen**: Is less potent because it has a slower rate of binding to the receptor. ## Response - This describes the effect of a drug on the body. - There are two types of responses: - **Graded response**: The response is proportional to the dose. - **Quantal response**: The response is either "all or none," or "completely affected or not affected." - The response determines the efficacy and potency of a drug. ## Receptors - **Receptors with an endogenous ligand**: - The ligand is a substance normally found in the body. - This type of receptor is usually activated by endogenous ligands. - **Receptors without an endogenous ligand**: - Such receptors are usually activated by exogenous ligands, such as drugs. ## Conclusion Understanding drug design and mechanisms of action is crucial for developing safe and effective drugs. The concepts discussed above are fundamental to pharmaceutical research and development.