Drug Design - Lead Discovery PDF

Lead Discovery  Lead Discovery Starting point of the Medicinal chemistry and second step of the drug discovery Sources of Lead Compounds Lead compounds can be acquired from a variety of sources: 1. Endogenous ligands, e.g., substrates for enzymes and transport...

Lead Discovery  Lead Discovery Starting point of the Medicinal chemistry and second step of the drug discovery Sources of Lead Compounds Lead compounds can be acquired from a variety of sources: 1. Endogenous ligands, e.g., substrates for enzymes and transporters or agonists for receptors; 2. Other known ligands, including marketed drugs 3. Screening of Compounds 4. Compounds isolated in drug metabolism studies 5. Compounds used in clinical trials; and 6. Chemical libraries, either at random or in a targeted approach. Lead Discovery  Endogenous Ligands Endogenous neurotransmitters Parkinson’s disease and restless leg syndrome Harmones Hormones are another important class of endogenous substances that have served as lead compounds for drug discovery. Contraceptives Serotonin receptor progesterone 17β-estradiol Lead Discovery  Endogenous Ligands Peptides constitute another broad class of hormones. Peptides usually cannot be delivered orally because of low permeability across gut membranes (as a result of their charge and polarity) and because of instability to gut peptidases. However, incorporation of disulfide bonds to cross-link a peptide can confer enzymatic stability (Thickening of skin and enlargement of hands and feet from overproduction of growth hormone) Serotonin reuptake inhibitor Antidepressant drug Dopamine Mechanism Lead Discovery  Kinase Inhibitors Reaction catalyzed by the kinase class of enzymes. Kinases catalyze the transfer of the terminal phosphate group of ATP or related molecules acceptor to the group of a substrate, in this case, an alcohol (ROH). The hydroxyl group on the tyrosine residue of a substrate protein (protein tyrosine kinase). Thus, kinases have two substrates, ATP (the phosphate donor) and the phosphate acceptor. Many kinase inhibitors were ultimately designed based on the structure of ATP, for example, gefitinib, which is used for the treatment of lung cancer. EGFR Inhibitor Lung cancer Lead Discovery  Known ligands Hypercalcemia from Osteoporosis drug malignancy An antihypertensive Antidepressant drug, drug, is in clinical trials has been approved to as a treatment for treat chronic lower back Parkinson’s disease pain Remdesivir- Hepatitis C Covid-19 An important advantage to repurposed drugs is that whereas only 10% of new drugs in Phase I clinical trials and 50% of Phase III drugs make it to the market, the rates for repurposed drugs are 25 and 65%, respectively. Lead Discovery  Screening of Compounds Endogenous or other ligands may not be known for a target of interest and mostly they are large proteins. Known ligands for a target may not be well suited as starting points for discovery of drugs that will ultimately possess the desired properties. So, screening for leads has played a central role in drug discovery for decades. Relevant biological assay: The first requirement for a screening approach is to have a means to assay compounds for a particular biological activity, so that researchers will know when a compound is active. Biological assay is an analytical method used to measure the functional activity of a molecule on living organisms, tissue, or live cells. Mass spectrometry: NMR: Isothermal calorimetry: Fluorescent polarization: Lead Discovery  Screening of Compounds Until 1980, screening was on whole animals or whole organisms: Whole animals: Large quantities of test compound required and by the fact that the results depended on other factors apart from the inherent potency of the compound at its intended target (pharmacodynamics), For example, the ability of the compound to be absorbed, distributed, metabolized, and excreted (pharmacokinetics). Whole Organisms: you may identify a very potent compound for a target, but it may not have the ability to be absorbed or is rapidly metabolized. LCMS, 1HNMR, HTS Lead Discovery  Sources of Compounds for Screening Natural Products Nature is still an excellent source of drug precursors, or in some cases, of actual drugs. More than 60% of the anticancer and anti-infective agents that went on the market between 1981 and 2006 were of natural product origin or derived from natural products; Why? This may be a result of the inherent nature of these secondary metabolites as a means of defense for their producing organisms for example, a fungal natural product that inhibits cell replication may be produced by the fungus to act on potential invading organisms such as bacteria or other fungi. It has been suggested that small molecule natural products tend to target essential proteins of genes from organisms with which they coevolved, rather than those involved in human disease, and the reverse is true of synthetic drugs. Lead Discovery  Sources of Compounds for Screening An important goal of an organization that conducts many HTS campaigns across a variety of types of biological targets will be to construct a screening library of structurally diverse compounds. The assumption is that structurally similar compounds will have similar biological activities, and conversely, that structurally diverse collections will show divergent biological activities. But a protein can bind a set of structurally diverse molecules with similar potent binding affinities, and analogs closely related to these compounds can exhibit very weak binding. High-Throughput Organic Synthesis. Solid-Phase Library Synthesis. Solution-Phase Library Synthesis Lead Discovery Solid phase peptide synthesis (example) Lead Discovery Solid-Phase Library Synthesis-7 hydroxy benzo diazepines Solid-Phase Library Synthesis-4 alkoxy proline derivatives 17,000 discrete compounds  Solution-Phase Library Synthesis Parallel library synthesis of up to a few thousand compounds at a time can frequently be carried out entirely by solution-phase parallel methods. Step 1: Alkylation with alkyl halide, deprotection of acetal group and oxidative cleavage with NaIO4. In this solution-phase library synthesis, the subsequent reactions are run in parallel in microtiter plates. Workup can be accomplished sequentially using two different solid phase scavenger resins followed by filtration Step 2: Each aldehyde (2.30) is added to multiple wells of a microtiter plate and treated with different secondary amines under reductive amination conditions (NaBH(OAc)3) to give aminomethyl derivatives 2.31. Step 3: Reaction of products of 2.31 with an alcohol in the presence of hydrogen chloride to form hydroxyl ethers 2.32. The resulting residues are dissolved in 1,4-dioxane/ THF and treated with polystyrene- bound piperidine to remove residual HCl; Solution-Phase Library Synthesis  ADME Absorption/administration: The process of a drug entering into systemic circulation from the site of administration. For a compound to reach a tissue, it usually must be taken into the bloodstream – often via mucous surfaces like the digestive tract (intestinal absorption) – before being taken up by the target cells. Factors such as poor compound solubility, gastric emptying time, intestinal transit time, chemical instability in the stomach, and inability to permeate the intestinal wall can all reduce the extent to which a drug is absorbed after oral administration. Absorption critically determines the compound's bioavailability. Drugs that absorb poorly when taken orally must be administered in some less desirable way, like intravenously or by inhalation (e.g. zanamivir). Routes of administration are an important consideration. Distribution: The dispersion or dissemination of substances throughout the fluids and tissues of the body. The compound needs to be carried to its effector site, most often via the bloodstream. From there, the compound may distribute into muscle and organs, usually to differing extents. After entry into the systemic circulation, either by intravascular injection or by absorption from any of the various extracellular sites, the drug is subjected to numerous distribution processes that tend to lower its plasma concentration. Distribution is defined as the reversible transfer of a drug between one compartment to another. Some factors affecting drug distribution include regional blood flow rates, molecular size, polarity and binding to serum proteins, forming a complex. Distribution can be a serious problem at some natural barriers like the blood–brain barrier.  ADME Metabolism: The chemical reactions of the drug and irreversible breakdown into metabolites Compounds begin to break down as soon as they enter the body. The majority of small-molecule drug metabolism is carried out in the liver by redox enzymes, termed cytochrome P450 enzymes. As metabolism occurs, the initial (parent) compound is converted to new compounds called metabolites. When metabolites are pharmacologically inert, metabolism deactivates the administered dose of parent drug and this usually reduces the effects on the body. Metabolites may also be pharmacologically active, sometimes more so than the parent drug (see prodrug). Excretion: The removal of the substance or metabolites from the body. Compounds and their metabolites need to be removed from the body via excretion, usually through the kidneys (urine) or in the feces. Unless excretion is complete, accumulation of foreign substances can adversely affect normal metabolism. There are three main sites where drug excretion occurs. The kidney is the most important site and it is where products are excreted through urine. Biliary excretion or fecal excretion is the process that initiates in the liver and passes through to the gut until the products are finally excreted along with waste products or feces. The last main method of excretion is through the lungs (e.g. anesthetic gases). The route of administration critically influences ADME.  Drug-Like, Lead-Like, and Other Desirable Properties of Compounds for Screening Lead compounds require optimization with respect to not only their activity against a biological target but also a number of pharmacokinetic parameters, including ADME characteristics. If these properties could be predicted from the structure of a compound, then they could be taken into account at an early stage, even including the design and selection of compounds for a screening collection. Oral bioavailability: Oral bioavailability (F%) is the fraction of an Lipinski proposed the Rule of 5 oral administered drug that reaches systemic circulation. The MW is