Computer Aided Drug Design (CADD) has now become an indispensable tool in the long process of drug discovery and development. It includes finding, developing and analyzing medicines and related biological active compounds by computer methodologies.
The reliability of the mathematical methods used to obtain and solve the equations is well known and so in most cases it is possible to obtain a reliable estimate of the accuracy of the results. In some cases the calculated values are believed to be more accurate than the experimentally determined figures because of the higher degree of experimental error in the experimental work.
There are two general types of computer-aided drug design (CADD) approaches in existence- Structure based drug design (SBDD) and ligand based drug design (LBDD). Consequently, in medicinal chemistry, it is now possible to visualize the three dimensional shapes of both the ligands and their target sites. In addition, sophisticated computational chemistry packages also allow the medicinal chemist to evaluate the interactions between a compound and its target site before synthesizing that compound.
Molecular modelling methods
The three dimensional shapes of both ligand and target site may be determined by X-ray crystallography or computational methods. The most common computational methods are based on either molecular or quantum mechanics. Both these approaches produce equations for the total energy of the structure. In these equations the positions of the atoms in the structure are represented by either Cartesian or Polar coordinates.
Once the energy equation is established, the computer computes the set of coordinates which correspond to a minimum total energy value for the system. This set of coordinates is converted into the required visual display by the graphics package.
Quantum mechanics calculations are more expensive to carry out because they require considerable more computing power and time than molecular mechanics calculations. Consequently, molecular mechanics is the more useful source of the large structures of interest to the medicinal chemist.
In molecular modelling the data produced are converted into visual images on a computer screen by graphics packages. These images may be displayed as space fill, CPK (Corey–Pauling–Koltun), stick, ball and stick, mesh and ribbon. Ribbon representations are usually used to depict large molecules, such as nucleic acids and proteins. Each of these formats can, if required, use a colour code to represent the different elements.
Molecular mechanics is the more popular of the methods used to obtain molecular models as it is simpler to use and requires considerably less computing time to produce a model. The molecular mechanics method is based on the assumption that the relative positions of the nuclei of the atoms forming a structure are determined by the forces of attraction and repulsion operating in that structure.
It assumes that the total potential energy (ETotal) of a molecule is given by the sum of all the energies of the attractive and repulsive forces between the atoms in the structure. These energies are calculated using a mechanical model in which these atoms are represented by balls whose mass is proportional to their relative atomic masses joined by mechanical springs corresponding to the covalent bonds in the structure. Using this model, ETotal may be expressed mathematically by equations, known as force fields. These equations normally take the general form:
- EStretching is the bond stretching energy,
- EBend is the bond energy due to changes in bonding angle,
- ETorsion is the bond energy due to changes in the conformation of a bond,
- EvdW is the total energy contribution due to van der Waals forces, and
- ECoulombic the electrostatic attractive and repulsive forces operating in the molecule between atoms carrying a partial or full charge.
Molecular dynamics programs allow the modeler to show the dynamic nature of molecules by simulating the natural motion of the atoms in a structure. This motion, which is time and temperature dependent, is modelled by including terms for the kinetic energy of the atoms in the structure in the force field by using equations based on Newton’s laws of motion.
Unlike molecular mechanics, the quantum mechanical approach to molecular modelling does not require the use of parameters similar to those used in molecular mechanics. It is based on the realization that electrons and all material particles exhibit wavelike properties. This allows the well-defined, parameter free, mathematics of wave motions to be applied to electrons, atomic and molecular structure. The basis of these calculations is the Schrodinger wave equation, which in its simplest form may be stated as:
HѰ = EѰ
Where, Ѱ is a mathematical function known as the state function or time dependent wave function, which defines the state (nature and properties) of a system.
The three dimensional structures produced on a computer screen may be manipulated on the screen to show different views of the structures. With more complex molecular mechanics programs it is possible to superimpose one structure on top of another. In other words, it is possible to superimpose the three dimensional structure of a potential drug on its possible target site. This process, which is often automated, is known as docking. It enables the medicinal chemist to evaluate the fit of potential drugs (ligands) to their target site.
Docking procedures have also been adapted to design possible leads. The computer is used to fit suitable structural fragments into the docking area. These fragments are joined to make molecules that fit the docking site. This procedure is referred to as De novo design.