Hypothetical active site lattice

Doweyko, A.M. (1991). The Hypothetical Active Site Lattice-in Vitro and in Vivo Explorations Using a Three-Dimensional QSAR Technique. J.MathChem., 7,273-285. 

Wiese, M. (1993). The Hypothetical Active-Site Lattice. In 3D QSAR in Drug Design. Theory, Methods and Applications. (Kubinyi, H., ed.), ESCOM, Leiden (The Netherlands), pp. 431-442. 

Doweyko, A. M. The hypothetical active site lattice. An approach to modeling active sites from data on inhibitor molecules. J. Med. Chem. 1988, 31, 1396-1406. 

Doweyko, A.M. (1991) The hypothetical active site lattice - in vitro and in vivo explorations using a three-dimensional QSAR technique. J. Math. Chem., 7, 273-285. 

Woolfrey, J.R., Avery, M.A. and Doweyko, A.M. (1998) Comparison of 3D quantitative structure-activity relationship methods analysis of the in vitro antimalarial activity of 154 artemisinin analogues by hypothetical active-site lattice and comparative molecular field analysis./. Comput. Aid. Mol. Des., 12, 165-181. 

The methods applied in recent years by various groups to construct QSAR models for ART and analogues include docking calculations to heme [104, 105], CoMFA [106-109] and hologram QSAR [108] as well as the hypothetical active-site lattice (HASL) approach [107], self-organizing maps of the molecular electrostatic potential [110], quantum-similarity measures [111] and topological molecular connectivity descriptors [112]. 

The merging of data for a series of known inhibitors results in the construction of a HASL (Hypothetical Active Site Lattice) which serves to quantitatively and predictively model enzyme-inhibitor interaction. Details of the HASL methodology are discussed and the approach illustrated using E. coli dihvdrofolate reductase inhibitors. 

The hypothetical active site lattice (HASL) method (Doweyko 1988) identifies the points of the network associated to the atoms of the molecule of interest. Then it gives a fraction of the value of the biochemical property to these points. This fraction is characteristic of the analyzed molecule. By repeating the procedure for all the molecules in a given set, some points of the network acquire the summing of the assigned values that are different from null values. These points describe a structure as a map of the active site of the receptor macromolecule that interacts with the effector molecules. 

A. M. Doweyko, J. Med. Chem., 31, 1396 (1988). The Hypothetical Active Site Lattice. An Approach to Modelling Active Site from Data on Inhibitor Molecules. 

HASL (hypothetical active site lattice) is a lattice-based 3D-QSAR technique that distributes partial activities at molecular lattice points (defined within the van der Waals volume of each ligand). The sum of all points belonging to a particular molecule equals the target property of that compound. Its statistical engine is based on multilinear regression. As in CoMFA, a set of alignment rules (i.e., choice of conformers and superimposition criteria) must be provided, but no other information is used. 

A. Doweyko, /. Med. Chem., 31, 1396 (1988). The Hypothetical Active Site Lattice. An Approach to Modelling Active Sites from Data on Inhibitor Molecules. See also j. J. Kaminski and A. M. Doweyko,/. Med. Chem., 40,427 (1997). Antiulcer Agents. 6. Analysis of the in Vitro Biochemical and in Vivo Gastric Antisecretory Activity of Substituted Im-idazo[l,2-a]pyridines and Related Analogues Using Comparative Molecular Field Analysis and Hypothetical Active Site Lattice Methodologies. 

D-QSAR = three-dimensional quantitative structure-activity relationship 3D-SAR = three-dimensional structure-activity relationship CoMFA = comparative molecular fields analysis DG = distance geometry HASL = hypothetical active-site lattice MLR = multiple linear regression MSA = molecular shape analysis PLS = partial least-squares. 

Ligand structures can be represented by molecular fields (electrostatic or steric), which contain enthalpic contributions to binding when implemented by conventional comparative molecular field analysis (CoMFA) (see Comparative Molecular Field Analysis (CoMFA)). Steric volume incorporated in molecular shape analysis (MSA) (Figure la) is another representation commonly used in SAR studies (see Molecular Surface and Volume) Alternatively, in the hypothetical active site lattice (HASL) approach, molecules are represented by a three-dimensional grid of points (lattice) associated with discrete electronic properties. ... 

---