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Chapter 10 | Lead Discovery Chapter 10 Lead Discovery Chapter Outline 10.1 Approaches to Searching for Hits • Lipinski’s Rules and Related Indices • Traditional Library Screening • Final Concerns for Promotion of a Hit • Fragment-Based Screening to a Lead • Virtual Screening 10.3 Special Cases 10.2 Filtering Hits to Leads • Serendipity • Pharmacodynamics and • Clinical Observations Pharmacokinetics • Natural Products • Biological Assays Once a target, normally an enzyme or receptor, has been established and an assay for activity has been developed, the medicinal chemistry team must discover, find, and Learning Goals make compounds that interact with the target. Through the screening process, some for Chapter 10 compounds emerge with sufficient activity to warrant further investigation. The active • Appreciate the role compounds are then examined against a number of criteria, including complexity and that screening of anticipated pharmacokinetic behavior. Compounds that satisfy the selection criteria are chemical libraries plays called leads and advanced for further optimization of activity, selectivity, and biologi- in drug discovery cal behavior. Occasionally, leads are found through other methods, such as serendipity • Distinguish between or clinical observations. This chapter describes techniques of discovering active com- the different library pounds through screening and selecting the most promising compounds as leads. The screening approaches overall process is collectively known as lead discovery. • Differentiate hits and leads • Know the properties that allow some hits to 10.1 Approaches to Searching for Hits be advanced as leads The most common tool for discovering hits is library screening. The library may consist over others of traditional compounds with potentially high activity molecules, smaller fragments of • Understand the non- less activity, or even virtual molecules tested through molecular modeling simulations. screening approaches that can produce leads Traditional Library Screening The goal of screening of a library, in whole or in part, is to discover compounds with modest activity against a target. The active compounds discovered through a screen are called hits. The threshold for activity varies based on the target, but hit-level activity is typically 1 mM or lower. Targets are normally enzymes or receptors, so the term activity refers to an IC50 or EC50 value. 247 M10_STEV0482_01_SE_C10.indd 247 10/26/12 7:16 PM 248 Chapter 10 | Lead Discovery General Aspects Compounds are normally stored as a stock solution to be dispensed as needed by robotic equipment. Dimethylsulfoxide (DMSO) is a preferred solvent for several reasons. First, in low concentrations, DMSO is well tolerated in most assays. Second, the low melting point of DMSO (18 ЊC) allows samples to be easily frozen. Compounds that are stored in the solid state are less prone to decompose. Third, DMSO is less volatile than most organic solvents. Decreased volatility minimizes solvent evaporation, so concentrations remain nearly constant over prolonged storage. Maintaining a known concentration is vital. The activity of each screened molecule is related by a concentration-effect relationship. If the concentration of a stock solution is not accurate, then any subsequent assessment of activ- ity will also be incorrect.1 The purity of compounds in the library is an important factor. Reaction side products (e.g., triphenylphosphine from a Wittig reaction) should be completely removed from a compound in a library. Similarly, compounds should be free of any solvents used in their synthesis. Unfortunately, not all impurities are easily removed. Impurities can sometimes interfere with an assay and lead to inaccurate results.2 Some reactions afford mixtures of products. Mixtures include diastereomers, such as endo and exo products (10.1 and 10.2) of a Diels-Alder cycloaddition, and regioisomers, such as ortho and para products (10.3 and 10.4) from an electrophilic aromatic substitution (Scheme 10.1). Even a reaction that forms products as subtly similar as enantiomers is tech- nically a mixture of products. Isomeric mixtures violate the spirit of “one compound, one well” in combinatorial chemistry. Isomeric mixtures, however, are often unavoidable and therefore tolerated in compound libraries. Mixtures are also tolerated in libraries of com- pounds that have been derived from natural sources. Examples include extracts from finely ground vegetation and microbial broths. Recall from Chapter 2 that high-throughput screens involve some type of biochemi- cal test for binding of the molecule of interest to a target. The screens are performed in 96-, 384-, or 1,536-well microtiter plates. As a library is screened, small amounts of each member of the library will be placed in each well and tested for activity. If each library member is a single compound, a well will contain a single compound or a mix- ture of compounds. Regardless of whether a library consists of single compounds or mix- tures, promising hits in an assay must have their activity confirmed. Confirmation testing involves identifying the library member, synthesizing that molecule, and repeating the 1 1 heat CO H diastereomers 2 H CO2H CO2H H endo product exo product 10.1 10.2 Br HO HO HO Br 2 1 regioisomers Br ortho product para product 10.3 10.4 Scheme 10.1 Isomeric products often found in libraries M10_STEV0482_01_SE_C10.indd 248 10/26/12 7:16 PM 10.1 Approaches to Searching for Hits | 249 assay. This process ensures that pure material of a known structure is used in the screen. The testing of pure material also ensures that the activity data is as accurate as possible. If the hit contains a mixture of compounds, each component of the mixture may need to be synthesized to determine which is responsible for the observed activity in the assay. All screening processes generate some irreproducible data, either false positives or false negatives. False positives are inactive compounds that erroneously give a positive result in an assay. False negatives correspond to compounds that are active in an assay yet mistakenly show up as inactive or weakly active. False positives are preferred to false negatives in a screen. A false positive will be quickly identified through follow-up confir- mation testing. Repeated testing will correctly show the false positive as inactive. In con- trast, inactive compounds, including false negatives, are almost never retested. Therefore, the true activity of a false negative will likely never be discovered, and a promising hit, and possibly a drug, may be completely missed. An important idea of a compound library is that it can be used over and over again in different assays. A pharmaceutical company may screen its library against a receptor one week and an enzyme the next week. A high-throughput screen (HTS) requires little sam- ple. Even a few milligrams of a molecule, when diluted into DMSO, will provide enough stock solution for many assays. The entire library is not normally tested in each assay. Preliminary information, such as x-ray or NMR data, on the target may allow some com- pounds to be eliminated from the screen based on physical properties (polarity, charge, size) or chemical structure. If less information is known about a target, the odds of the entire library being screened become greater. The cost of an inexpensive high-throughput screen may be as low as US$0.10 per well, so screening a large library of a million com- pounds would be $100,000 or more. This may be a small price to pay for information that affords hits that can be optimized into a marketable drug, but a marketable drug is not a sure outcome of every large-scale screening. In summary, compound libraries are a vital resource in a productive drug discovery program. Molecular biological information on a target can advance a drug search only so far. Random screening of either an entire or partial library, then, hopefully provides promising hits for the lead optimization stage. In-house Libraries As medicinal chemists synthesize molecules during their day-to-day research, small samples of new compounds are submitted for inclusion in the company’s compound library. Over the course of years and decades of research, a compound library steadily grows. A library will reflect the areas of research that have contributed to the collec- tion. A company that has historically been strong in researching b-lactam antibiotics (10.5 and 10.6) would have a very different library from a company with strength in estrogen receptor binding compounds (10.7 and 10.8) (Figure 10.1). Once combinato- rial chemistry became recognized in the 1990s as a method for making large numbers of molecules, most pharmaceutical companies hired teams of chemists to create collections of molecules to augment the company’s existing library. Samples from natural sources may also be included in a library. When pharmaceutical companies merge, their libraries merge as well. Through a library, the purchasing company gains a tangible chemical record of the research of the acquired firm. In 1995, Glaxo acquired Wellcome. An area of strength for Wellcome was antiviral research. Wellcome’s products at the time included acyclovir (10.9) and zidovu- dine (AZT, 10.10), nucleoside analogues with activity against the herpes simplex and hu- man immunodeficiency viruses, respectively (Figure 10.2). Today, Glaxo, now operating under the name GlaxoSmithKline (GSK), still maintains a strong presence in treatments M10_STEV0482_01_SE_C10.indd 249 10/26/12 7:16 PM 250 Chapter 10 | Lead Discovery Figure 10.1 b-Lactam NH2 antibiotics (10.5 and 10.6) and H H H H N S estrogens (10.7 and 10.8) Ph N S Ph O N O N O Cl O CO2H CO2H cefaclor penicillin G (Ceclor) antibiotic antibiotic 10.5 10.6 OH S Me OH H N H H HO O O HO raloxifene estradiol (Evista) hormone estrogen receptor ligand 10.7 10.8 Figure 10.2 Antiviral O NH2 compounds O Me HN N N NH HO O N HO O N HO N N NH2 O S O O N3 acyclovir zidovudine lamivudine (Zirovax) (Retrovir) (Epivir) 10.9 10.10 10.11 for viral infections.
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