## Scoring Functions for Protein Ligand Docking

It is often useful to make a distinction between docking and scoring in structure-based virtual screening experiments. Docking involves the prediction of the binding mode of individual molecules, the aim being to identify the orientation that is closest in geometry to the observed (x-ray) structure. Several studies have been performed to evaluate the performance of docking programs using data sets derived from the PDB and it is found that these programs are able to correctly predict the binding...

## Pharmacophore Keys

Pharmacophore keys are an extension of the 3D screens developed for 3D pharmacophore searching Pickett et al. 1996 . They are based on pharmacophoric features, that is, atoms or substructures that are thought to have relevance for receptor binding. Pharmacophoric features typically include hydrogen bond donors, hydrogen bond acceptors, charged centres, aromatic ring centres Figure 3-4. The generation of 3-point pharmacophore keys, illustrated using benperidol. Two different conformations are...

## Pharmacophore Mapping Using a Genetic Algorithm

Genetic algorithms (GAs) are a class of optimisation methods that are based on various computational models of Darwinian evolution Goldberg 1989 (the term evolutionary algorithms is also used to describe such methods). GAs have found widespread use in many fields including computational chemistry and chemoinformatics Clark and Westhead 1996 Jones 1998 Clark 2000 we will discuss applications in protein-ligand docking, the generation of Quantitative Structure-Activity Relationships (QSAR) models,...

## Theoretical 3d Databases

Experimental databases such as the CSD are extremely valuable sources of information, but for most compounds no crystal structure is available. There is also an increasing need to evaluate virtual compounds - structures that could be synthesised (e.g. using combinatorial chemistry) but which have not yet been made. Even when experimental data is available, this usually provides just a single conformation of the molecule which will not necessarily correspond to the active conformation most...

## Interpretation and Application of a QSAR Equation

The ultimate value of a QSAR model, of course, depends on the impact that it has on the direction of the project. The most obvious use of a QSAR is in predicting the activity of molecules not yet synthesised. Prediction can be interpolative or extrapolative Tute 1990 . An interpolative prediction is one within the range of properties of the set of molecules used to derive the QSAR an extrapolative prediction is one beyond it. Interpolative prediction is generally more reliable than...

## Properties of Similarity and Distance Coefficients

For certain types of calculations it is important to know whether a distance coefficient is a metric. To be described as such, four properties must be met 1. The distance values must be zero or positive, and the distance from an object to itself must be zero DAB gt 0 DAA DBB 0 2. The distance values must be symmetric DAB DBA 3. The distance values must obey the triangle inequality DAB lt DAC DBC 4. The distance between non-identical objects must be greater than zero The Hamming, Euclidean and...

## Algorithms for Subgraph Isomorphism

Having eliminated molecules using the bitstring screen the subgraph isomorphism search is then performed on the molecules that remain to determine which actually match the substructure. The subgraph isomorphism search is inherently slower indeed it belongs to a class of problems known as NP-complete, meaning that to find a solution all algorithms require an amount of time that varies exponentially with the size of the problem which for subgraph isomorphism corresponds to the number of nodes in...

## Conformation Energy Calculations And Energy Surfaces

The conformations of a molecule are the 3D structures that it can adopt. Conformational analysis is the study of the conformations of a molecule and their influence on its properties. Different conformations of a molecule arise from changes in bond lengths, bond angles and torsion angles defined in Figure A2-1 . Rotations about single bonds usually give rise to the most significant changes in conformation and also require the least energy. For this reason it is common when performing a...

## Pharmacophore Mapping Using Constrained Systematic Search

The constrained systematic search approach has its origins in the development of efficient algorithms for systematically exploring conformational space Motoc et al. 1986 . As explained in the discussion on systematic conformational search methods, such procedures have an exponential dependence on the number of rotatable bonds in the molecule. By making use of tree-pruning methods described earlier to eliminate unfavourable, high-energy conformations the efficiency of these algorithms can be...

## BCUT Descriptors

BCUT descriptors were designed to encode atomic properties relevant to intermolecular interactions. They have been used extensively in diversity analyses. BCUT values are based on an earlier descriptor developed by Burden 1989 that is calculated from a matrix representation of a molecule's connection table. The atomic numbers of the non-hydrogen atoms are placed on the diagonal of the matrix. The off-diagonals are assigned the value 0.1 times the bond type if the atoms are bonded, and 0.001 if...