Drug Design (PC 710) Lecture Notes PDF

Drug Design (PC 710) Lecture Effect of Physicochemical properties on the PK Profile by: Prof. Hanan Hanna Georgey Dr. Mai Hatem Mousa Office Hours: Monday: 10:30-12:30...

Drug Design (PC 710) Lecture Effect of Physicochemical properties on the PK Profile by: Prof. Hanan Hanna Georgey Dr. Mai Hatem Mousa Office Hours: Monday: 10:30-12:30 Sunday: 10:30-12:30 Thursday: 10:30-12:30 Wednesday: 10:30-12:30  Physicochemical Properties in relation to Drug Action/ Biological Activity For a drug to bind to the receptor it must have certain physiochemical properties Physiochemical properties affects the 1. Based on Reaching site of action ability to: 2. Affinity + Activity Biological Activity Structure and Physicochemical Properties – Affected by : pKa Structure and Solubility Physicochemical Steric properties Factors Bulkiness Polarity BBB Structure & Physicochemical properties 4 Example Polarity CH3 CH3 H3C CH3 CH2CH=CH2H3 N N + N N O O O HO OH HO OH AcO OAc HO O OH Morphine Inactive Heroin (more potent) Nalorphine(morphine antagonist) Active cross Ionized, can not Acetyl= More Bulky= BBB cross BBB Lipophilic better Antagonist cross BBB  Drug-likeness The lead compound to be orally bioavailable: Lipinski's rule of five: (multiples of five) 1. A molecular mass less than 500 2. A log P not greater than 5 3. No more than 5 hydrogen bond donors (the total number of nitrogen-hydrogen and oxygen-hydrogen bonds) 4. No more than 10 hydrogen bond acceptors (all nitrogen or oxygen atoms) 5. 10 or fewer rotatable bonds 6. Polar surface area (PSA) not greater than 140 Ǻ2 TPSA: Provides an indication of the drug’s polarity (N2 & O2), and thus an indication of its lipid solubility. Units of Ångströms increases as the number of polar groups within the drug structure increases  In-silico prediction 6 ❑ To predict the oral bioavailability and other pharmacokinetic parameters, few free online tools are available such as: (covered in Practical) A- SwissADME.com B- Molinspiron.com  ADME properties 7 Storage sites Parentral route Site of action Circulation GIT Metabolism Excretion Physicochemical properties affect 1. Absorption 2. Distribution ADME 3. Metabolism 4. Excretion  Route of Administration 8 Parenteral GIT **There is no absorption barrier in case of IV, Drug absorption. intra-arterial or Is affected by: intraspinal. **pH Stomach pH: 1-3.5 **The drug has to pass Duodenum pH: 6-7 some membrane barriers Lower ileum pH: 8 till it reaches the **Dissociation rate of the circulation in case of IM, drug at that pH. SC, ID, IP. Intraperitoneal injection , Intradermal  1. Absorption 9 “It is the transportation of molecules across cell membranes.” Types of Drug Absorption: 1. Passive Diffusion 2. Active transport (or) Carrier mediated transport 3. Convective absorption  Types of Drug Absorption 10 1. Passive Diffusion: The movement of drugs occur following the concentration gradient (from high → low concentration). 2. Active transport (or) carrier mediated transport: Energy is required as it occurs against concentration gradient. Also, there should be structural similarity between the drug and the substrate normally carried across the membrane. 3. Convective absorption: Where small molecules of molecular radius less than 4 Ǻ pass through water filled pores in the biological membrane. ‫زي المص ف‬ Ex. Grisiofulvin micronized capsules