Computers have influenced all aspects of our daily life and science is no exception. Recent progress in computer hardware, its accessibility, and the explosive growth of its software base, have made computers indispensable research tools. There are many aspects of medicinal chemistry where computer analysis and simulation can augment or explain experimental observations. From analysis of enzyme kinetics, through designing optimal synthetic paths, to calculations of free energy of binding, computers and sophisticated software packages are inseparable partners with the modern medicinal chemist. Chemical intuition and experience will always be necessary, but computers add depth and new dimension in the search for better drugs. For excellent reviews on the status of computational chemistry and its relevant applications to computer assisted molecular design consult Lipkowitz and Boyd, (1990, 1991).
The impact of computers was felt very early in this discipline. Quantitative Structure Activity Relationships (QSAR), as described in Chapter 3, originated in the early sixties. It was a very successful method in optimizing the activity of drug molecules which required the use of the computer. The QSAR method in its original form was only applicable to congeneric series of drug molecules (i.e., molecules having the same backbone). The QSAR method is still a very active field of research in medicinal chemistry and with the parallel development in multivariate statistical analysis and theoretical chemistry, the method is being extended to noncongeneric series of biologically active molecules, where simple parameters used earlier are now estimated from theory or replaced by more sophisticated indices.
Probably the most spectacular impact on medicinal chemistry is due to advances in computer graphics. With computer graphics tools we now can generate molecular models from rough sketches, display molecular surfaces and charges, inspect these models, and manipulate them in three dimensions. Our psychological perception of the molecule has been changed from a lifeless chemical formula to a lively and colorful object on a computer screen with personality and character.
It is not possible to present all aspects of computer applications to medicinal chemistry in a chapter. Moreover, each problem is unique and requires a special set of tools and methods depending on the available experimental results and existing insight. Different methods are used to design drugs when their molecular targets are known, and other methods are needed when the chemical nature of the drug receptor is unknown. This chapter will focus on practical issues of using molecular modeling systems and will introduce basic terminology and theoretical background. The examples of practical drug design applications will not be described here, since there are many excellent reviews on this topic.
In general, molecular modeling systems are computer programs which allow: building molecules from fragments (e.g., residues) and groups; displaying different graphic representations of molecules; translation and rotation of molecular objects on the screen; modifying molecular models by changing distances, angles and replacing/adding atoms and groups; refining geometry of molecules by molecular mechanics or similar methods; superimposing and comparing molecular objects; computation and display of molecular volumes, surfaces, electrostatic potentials and other properties; and preparing plots on various hardcopy devices. Molecular modeling systems also incorporate, or help in preparing, input data for specialized programs like molecular mechanics, dynamics, conformational searches, quantum methods, databases of chemical information, etc. They also provide means for the analysis and visualization of results from other specialized programs.
Digital computers know only about two values: TRUE and FALSE, in other words, they represent all data and instruction as binary numbers. Any size number can be represented as a binary number, e.g., 9 (nine) is binary 1001, and 195 is binary 11000011. Letters are also coded as numbers by assigning to each letter a specific number. The most popular table of such assignments is called the ASCII table, for example, letter ``a'' has a code 97, while the code for the digit ``9'' is 57. There are many ways of representing pictures. Currently the most popular raster graphics devices represent a picture as a dense matrix of individual dots (pixels), each of them with its own color. The most natural way of representing such raster pictures is to specify a numerical value of the color associated with each pixel, since colors are also assigned specific numbers in the computer. Instructions (i.e., a computer program) for the processor of the computer are also coded as binary numbers. Binary numbers are stored either in the internal, fast memory of the computer, or externally on the magnetic tape or disk. The internal memory is volatile and holds data only when a program is running. For permanent storage, chemical information must be saved on some external medium. In early systems these were perforated tapes or cards. Now, a magnetic or optical disk, or a magnetic tape is used offering much higher information density, durability and versatility of use.
The next sections describe some of the methods used to represent chemical data for computations, or specifically, how molecular structures and properties can be converted to a numeric form suitable for the computer. Also, theoretical background of some computational approaches will be presented.