Compound registration

Every chemical company or research organization has a collection of compounds of interest. These may be compounds synthesized by chemists employed at the company, compounds purchased from chemical vendors, compounds on which research has been carried out, or any other collection of compounds. When a new compound becomes of interest, it is important to know whether that compound has already been entered into the system, or a new entry needs to be made. The use of canonical SMILES as a unique name for each structure makes this an easy task. One essential table in a compound registration system is a table of unique structures. Such a table could be defined as follows. 

Create Function add new structure() Returns Trigger As EOSQL Begin 

Create Trigger add new structure Before Insert Or Update On structure For Each Row Execute Procedure add new structure()  

Create Index cansmi index On structure (cansmi)  

The next statement defines a t r igger function that will be used whenever data is inserted or updated in this table. This function performs three important functions. First, it modifies the SMILES to be inserted into the smi column so that it contains the result of the isosmiles function. The isosmiles function is similar to the cansmiles function, except that it retains any stereochemistry that might be contained within the SMILES. If two stereoisomers are entered into this table, each will have a unique isosmiles value, but the same cansmiles value. In this way, they can be kept distinct, but their identical canonical SMILES shows them to be stereoisomers. The trigger function also computes the fingerprint and inserts it into the table when the SMILES is inserted or updated. 

---

Compound Registration. A common step in a chemical synthesis experiment is the reaction of one or more existing molecules to form a desired product. This necessitates selecting molecules from a chemical database or repository and registering the target molecule into that same chemical database or... 

Obviously a compound registration system is already a fundamental part of the informatics infrastructure for any pharmaceutical company. However, there is a powerful efficiency gain in not having scientists input information twice into different systems the reaction information into the ELN and then the product molecules into the registration system. One would rather have a mechanism of pushing the product molecule information from the ELN to the registration system. The obvious corollary to this is to have the ability to retrieve compound information from the registration system and have it automatically entered into the ELN—an example would be for the scientist to... 

As one of the indispensable software tools, the compound registration system provides a mechanism for the medicinal chemist to capture chemical structure information as well as analytical and other data in a database. We mention two of the systems below. 

Service-oriented architecture (SOA) is a hot topic these days and is considered by many people to be the enterprise computing framework of the future. In SOA, each software unit runs on a piece of hardware as a service that can be called by many different consumers. For example, a compound registration service can be called by a library enumeration tool and a chemistry e-notebook to fulfill compound registration tasks. The most popular SOA is Web services that are based on HTTP and XML or SOAP standards although SOA as a concept has existed for awhile and is not limited to Web services. SOA has a lot of advantages, the most important of which is code reuse and improved productivity. However, it also presents a lot of challenges. 

System makes sure all required data are entered (see Compound Registration Required and Optional Data Supplement). System performs uniqueness check against the database (see Uniqueness Check Business Rules Supplement). If the structure is unique, System registers the compound with a new sample identifier (see Sample Identifier Generation Rules Supplement). If it is not unique, System displays the compound to be registered and the hit compounds from uniqueness search and prompts die Chemist to resolve (see Resolve Compounds Use Case Spec). 

A domain object model is a model that describes key domain concepts and their relationships. Many of these concepts come from tangible objects in the real world of the problem domain. In the chemical informatics space, these are the objects that chemists are dealing with on a daily basis, such as compounds, structures, notebooks, and libraries. The domain analysis model being presented here focuses on those objects that are involved in the compound registration process. 

Registration This is an abstraction that represents a compound registration transaction. A registration can be for a single compound, a group of discrete compounds, or a compound library. 

Structure This is the most important object in CRS. Getting structures correct is critical to the compound registration process. After being registered, the structures have to be searchable and linkable to biological... 

EJB, etc.) to do the actual work, because the action class is a Web component. It takes HTTP Request as an argument into its execute() method. Coding business logic in the action class makes it less reusable and difficult to test. Action Form is a Java Bean that holds user input from the HTML form. It has the setter methods that Struts uses to set its properties from the HTTP Request object. It also has getter methods that the action class uses to access these properties. Figure 11.3 illustrates a hypothetical compound registration transaction using the Struts framework. 

Figure 11.3 Compound registration in the Apache Struts framework.

The above workflow can very well be represented by a finite state machine—the compound object goes through a series of state transitions in the compound registration process. A finite state machine can be modeled using the UML State Diagram. Figure 12.4 is the UML State Diagram of a compound object. 

The last state of a compound in the compound registration context is Ready To Be Registered State. A compound is ready for registration when its structure passes chemistry convention rules and salts have been attached, and all required ancillary data, such as project and notebook information, have been entered. 

To increase productivity, a registration system should be able to register a compound library as a single transaction. Usually a compound library consists of a group of compounds that are synthesized using parallel synthesis, combinatorial chemistry, or compounds that are acquired from commercial or academic sources. From the compound registration perspective, a library can also be a group of compounds that share some common attributes such as a research project they are synthesized for, the chemist who synthesized them, the creation date, and the notebook information. 

In a compound registration system, compound data can be imported from data files such as SD File, XML File, or Mobile. Alternatively, data can be entered from the presentation layer using a structure drawing package such as ISISDraw or ChemDraw. These data, once imported to the system, need to be bound to the domain objects in order for the system to process them efficiently. To support a variety of data sources, a Data Binder API is needed to decouple the system from specific format of input data and make it easily extensible to support other data input formats down the road. Figure 12.17 is the class diagram of the Data Binder API. 

The last step of the compound registration workflow persists compound data into the database. This step is accomplished by a RegistrationService object along with a data persistence layer, which will be discussed in the next chapter. 

The compound registration process uses some reference data that do not change very often. Examples of these data are Research Projects, Assays, People, and Salts. These ancillary data are usually accessed by CRS using some lookup mechanism, such as by name, site, and id. 

The above entity dictionary module provides fast, in-memory access of most frequently accessed data for the compound registration process while keeping the in-memory cache up-to-date. In a multitiered system, controlling network traffic is critical to its speed and user experience. The above design eliminates the need of querying the database every time a piece of data is asked for, and since the system can use the cached dictionaries to display only the valid entities to the user, it also reduces human errors. 

One critical task of any compound registration system is to make sure molecular structures are compliant with chemistry conventions. This ensures consistent representations of molecular structures in the database so that structure searches can find, and only find, the right compounds. Although different organizations may have slightly different conventions, the following ones are some of the most common that the Chemistry Intelligence API takes care of. 

For each table in the database, a mapper object is needed. To manage a transaction that involves multiple tables, which is the case for compound registration, use a Unit of Work (Fowler, 2003b) object that groups die inserts and updates together. 

As mentioned above, one can purchase compounds already plated in microtiter plates from any of several vendors for 10-20 per mg of sample. The compounds are distributed on 96-well plates (see Fig. 1), allowing blank columns for positive (reference compound) and/or negative (solvent) controls. The plates are now frequently shipped with electronic plate maps on computer disks. These plate maps contain relevant information on structure and vendor ID numbers. Many pharma sites are now spending the time to solvate and distribute their existing compound libraries on microtiter plates. The compound ID numbers and plate maps can easily be imported into virtually any compound registration software system. This information can be linked to data analysis packages (see below) to provide a means of integrating structure and activity data. 

BIOSTAR Tripos Inc. (St. Louis, MO, U.S.A.) Macintosh -based (4-DL) Around S20K Compound registration, assay assignment, data analysis, data storage and retrieval, easy interface with chemical structure and diversity software offered by Tripos Only on Macintosh, difficult to customize, cannot execute cross-plate operations... 

---