Organic Chemistry - Drug Distribution & Computer Aided Drug Design PDF

Organic Pharmaceutical Chemistry Drug Distribution and pKa & Computer Aided Drug Design Organic| Drug Distribution and pKa Contents : Early Methods 8 Partition Coefficient 14 Newer Methods 26 Organic| Drug Distribution and pKa The pKa can have a pronounced effect on the pharmacokinetics of the drug....

Organic Pharmaceutical Chemistry Drug Distribution and pKa & Computer Aided Drug Design Organic| Drug Distribution and pKa Contents : Early Methods 8 Partition Coefficient 14 Newer Methods 26 Organic| Drug Distribution and pKa The pKa can have a pronounced effect on the pharmacokinetics of the drug. Drugs are transported in the aqueous environment of the blood. Those drugs in an ionized form will tend to distribute throughout the body more rapidly than will un-ionized (nonpolar) molecules. then, the drug must leave the polar environment of the plasma to reach the site of action by passing through the nonpolar membranes of capillary walls, cell membranes, and the blood-brain barrier in the un-ionized (nonpolar) form. Organic| Drug Distribution and pKa For HA acids, it is the parent acid that will readily cross these membranes. The situation is just the opposite for the BH+ acids. The unionized conjugate base (B, free amine) is the species most readily crossing the nonpolar membranes. Organic| Drug Distribution and pKa For drug molecules orally administered. The drug first encounters the acidic stomach, where the pH can range from 2 to 6 depending on the presence of food. HA acids with pKa’s of 4 to 5 will tend to be nonionic and be absorbed partially through the gastric mucosa. (The main reason most acidic drugs are absorbed from the intestinal tract rather than the stomach is that the microvilli of the intestinal mucosa provide a large surface area relative to that found in the gastric mucosa of the stomach.) Organic| Drug Distribution and pKa In contrast, amines (pKa 9–10) will be protonated (BH+ acids) in the acidic stomach and usually will not be absorbed until reaching the mildly alkaline intestinal tract (pH 8). Once in systemic circulation, the plasma pH of 7.4 will be one of the determinants of whether the drug will tend to remain in the aqueous environment of the blood or partition across lipid membranes into hepatic tissue to be metabolized, into the kidney for excretion, into tissue depots, or to the receptor tissue. Of course, the effect of protein binding, discussed previously, can greatly alter any prediction of biodistribution based solely on pKa. COMPUTER AIDED DRUG DESIGN CADD Organic| Computer Aided Drug Design A. Early Methods : Drug design is the process of finding new medicines for treating diseases. There are two main approaches to drug design: 1. The first one is based on modifying existing molecules, usually from natural sources, to make them more effective or less toxic. This approach has produced many important drugs, such as antibiotics, hormones, and painkillers. Organic| Computer Aided Drug Design 2. The second one is based on understanding the cause of the disease and the structure of the target where the drug will bind. This approach uses computer tools to predict the biological activity and the best fit of potential drugs. This approach is called quantitative structure–activity relationships (QSAR). QSAR plays a crucial role in drug design and discovery by establishing mathematical relationships between the chemical structure of compounds (through certain structural parameters) and their biological activities. Organic| Computer Aided Drug Design The main QSAR parameters include: 1. Molecular Weight: Influences pharmacokinetic properties, such as absorption, distribution, metabolism, and excretion (ADME). 2. Partition Coefficient: Partitioning between octanol and water. It reflects the compound's hydrophobicity and membrane permeability. Organic| Computer Aided Drug Design 3. Number of Hydrogen Bond Donor/Acceptor: Indicates the potential for forming hydrogen bonds. It influences the molecule's ability to form specific interactions with biomolecules (ex. Receptors). 4. Polar Surface Area: The surface area of a molecule that is polar and capable of forming hydrogen bonds. It affects interactions with biological targets and influences the compound's permeability Organic| Computer Aided Drug Design Some pharmacological concepts (biological activities parameters) that are useful for drug design are: 1. The ED50, which is the dose of the drug that produces the desired effect in half of the subjects. The lower the ED50, the more potent the drug is. 2. The ED90, which is the dose of the drug that produces the desired effect in 90% of the subjects. Organic| Computer Aided Drug Design 3. The LD50, which is the dose of the drug that kills half of the subjects. The lower the LD50, the more toxic the drug is. 4. The MIC, which is the lowest concentration of the drug that inhibits the growth of bacteria. The lower the MIC, the more effective the drug is against infections. Organic| Computer Aided Drug Design Partition Coefficient : The most common physicochemical descriptor is the molecule’s partition coefficient in an octanol/water system. As emphasized previously, the drug will go through a series of partitioning steps: A. leaving the aqueous extracellular fluids. B. passing through lipid membranes. C. entering other aqueous environments before reaching the receptor. Organic| Computer Aided Drug Design In this sense, a drug is undergoing the same partitioning phenomenon that happens to any chemical in a separatory funnel containing water and a nonpolar solvent such as hexane, chloroform, or ether. The partition coefficient (P) is the ratio of the molar concentration of chemical in the nonaqueous phase (usually 1-octanol) versus that in the aqueous phase. To obtain a linear correlation between partition coefficient and concentrations,it is more common to use the logarithmic expression. Organic| Computer Aided Drug Design A large percentage of drugs are amines whose pKa is such that at physiological pH 7.4, a significant percentage of the drug will be in its protonated, ionized form (BH+). A similar statement can be made for the HA acids (carboxyl, sulfonamide, imide) in that at physiological pH, a significant percentage will be in their anionic forms(A-). An assumption is made that the ionic form is water-soluble and will remain in the water phase of an octanol/water system. This reality has led to the use of log D, which is defined as the equilibrium ratio of both the ionized and un-ionized species of the molecule in an octanol/water system. Organic| Computer Aided Drug Design The percent ionization of ionized HA acids and BH protonated amines and acids can be estimated from previous equations and the log D become as follow: Organic| Computer Aided Drug Design Because much of the time the drug’s movement across membranes is a partitioning process, the partition coefficient has become the most common physicochemical property. The question that now must be asked is what immiscible nonpolar solvent system best mimics the water/lipid membrane barriers found in the body? It is now realized that the n-octanol/water system is an excellent estimator of drug partitioning in biological systems. Organic| Computer Aided Drug Design To appreciate why this is so, one must understand the chemical nature of the lipid membranes. These membranes are not exclusively anhydrous fatty or oily structures. As a first approximation, they can be considered bilayers composed of lipids consisting of a polar cap and large hydrophobic tail. Phosphoglycerides are major components of lipid bilayers. Other groups of bifunctional lipids include the sphingomyelins, galactocerebrosides, and plasmalogens. Organic| Computer Aided Drug Design Organic| Computer Aided Drug Design The hydrophobic portion is composed largely of unsaturated fatty acids, mostly with cis double bonds. In addition, there are considerable amounts of cholesterol esters, protein, and charged mucopolysaccharides in the lipid membranes. The final result is that these membranes are highly organized structures composed of channels for transport of important molecules such as metabolites, chemical regulators (hormones), amino acids, glucose, and fatty acids into the cell and removal of waste products and biochemically produced products out of the cell. Organic| Computer Aided Drug Design The cellular membranes are dynamic, with the channels forming and disappearing depending on the cell’s and body’s needs. Organic| Computer Aided Drug Design For this cell membrane, the two outer layers, one facing the interior and the other facing the exterior of the cell, consist of the polar ends of the bifunctional lipids. These surfaces are exposed to an aqueous polar environment. The polar ends of the charged phospholipids and other bifunctional lipids are solvated by the water molecules. There are also considerable amounts of charged proteins and mucopolysaccharides present on the surface. In contrast, the interior of the membrane is populated by the hydrophobic aliphatic chains from the fatty acid esters. Organic| Computer Aided Drug Design A partial explanation can be presented as to why the n-octanol/water partitioning system seems to mimic the lipid membranes/water systems found in the body. Water-saturated octanol contains 2.3 M water because the small water molecules easily cluster around octanol’s hydroxy moiety. The water in the n-octanol phase apparently approximates the polar properties of the lipid bilayer, whereas the lack of octanol in the water phase mimics the physiological aqueous compartments, which are relatively free of nonpolar components. Organic| Computer Aided Drug Design In contrast, partitioning systems such as hexane/water and chloroform/water contain so little water in the organic phase that they are poor models for the lipid bilayer/water system found in the body. At the same time, remember that the n-octanol/water system is only an approximation of the actual environment found in the interface between the cellular membranes and the extracellular/intracellular fluids. Organic| Computer Aided Drug Design B. Newer Methods : Computational chemistry methods in drug design involve the application of computational techniques and softwares to model and analyze the chemical interactions between drugs and their biological targets. These methods are used to: 1. Generating pharmacophores: A pharmacophore is a theoretical framework that represents the essential structural and chemical features necessary for a molecule to interact with a specific biological target and exhibit a particular biological activity. These features include hydrogen bond donors/acceptors, hydrophobic regions, aromatic moieties, and the relative spatial arrangement. Organic| Computer Aided Drug Design 2. Virtual High Throughput Screening (vHTS): is a computational approach used in drug discovery to rapidly assess large databases of chemical compounds in silico (using computer simulations), rather than through traditional experimental methods, to identify potential lead compounds with desired biological activity. Organic| Computer Aided Drug Design 3. Lead Compound Optimization: A lead compound is an actual chemical entity identified during the early stages of drug discovery that exhibits promising biological activity against a specific target. The lead compound serves as a starting point for further optimization and development into a potential therapeutic agent. Lead compounds are selected based on their ability to interact with a target and their potential for further modification to enhance properties like potency, selectivity, and pharmacokinetics. 4. In Silico ADME Modeling: Predicts the Absorption, Distribution, Metabolism, and Excretion (ADME) properties of drugs using computational methods.