Introduction

What is HASL?

HASL modeling is accomplished through the intermediate conversion of a superposed set of molecules to a set of regularly-spaced points (lattice) defined by Cartesian coordinates (x,y,z) and atom type. The resulting lattice is then related to individual molecular binding activity by endowing each lattice point with a partial binding value so that the sum of any set of points belonging to a particular molecule results in the original binding value for that molecule.

The HASL methodology has been successfully applied to a number of systems spanning in vitro and in vivo applications,including a remarkable reverse QSAR approach wherein the level of alkylation observed for a series of DNA 4-mers was related to potential uracil mustard binding (prior to alkylation reaction) near the target guanidine region to the extent that it was possible to identify key DNA functionalities responsible for the specificity of that binding.

Continuing work on the development of HASL has led to further refinements which now include the ability to construct a 3D-pharmacophore which not only identifies the moieties responsible for binding but also quantifies their relative binding contributions, thus highlighting important binding regions (both positive and negative). This information is of particular use in the computer-assisted rational design of bioactive molecules.

In addition, HASL has been demonstrated to have the same predictive and modeling capabilities as the widely accepted 3D-QSAR CoMFA (Sybyl; Tripos) approach. This was done by conducting HASL analysis on the same Cartesian coordinate data used for CoMFA modeling.

Typical uses for HASL include:

• Modeling the active site-inhibitor or active site-ligand interactions by construction of a hypothetical active-site lattice.

• Determining a three-dimenisional (3-D) pharmacophore that accurately predicts the activity of inhibitors or ligands.

• Determining a three-dimenisional (3-D) pharmacophore which identifies the moieties responsible for binding and quantifies their relative contributions.

• Calculating maps that allow visualization of interactions between drugs and receptors or within proteins.

Selected HASL References

1. The Hypothetical Active Site Lattice. An Approach to Modelling Active Sites from Data on Inhibitor Molecules. A.M. Doweyko, J. Med. Chem. 1988, 31, 1396-1406.

2. Three-Dimensional Pharmacophores from Binding Data. A.M. Doweyko, J. Med. Chem. 37, 1769-1778.

3. A New Tool for the Study of Structure-Activity Relationships in Three Dimensions. HASL: The Hypothetical Active Site Lattice. A.M. Doweyko In Bioactive Mechanisms: Proof, SAR and Prediction (ACS Symposium Series 413, 1989), ed. Philip S. Magee, Douglas Henry and John Block, American Chemical Society, Washington, D.C.

4. The Synthesis and Biological Activity of S-Alkyl Phosphohomocysteine Sulfoximides. M. Nowakowski, M. Tishler and A.M. Doweyko Phosphorus and Sulfur, 1989, 45, 183.

5. The Hypothetical Active Site Lattice - In Vitro and In Vivo Explorations Using a Three-Dimensional QSAR Technique. A.M. Doweyko J. Math. Chem. 1991, 7, 273.

6. The Hypothetical Active-Site Lattice Wiese, M. in 3D QSAR in Drug Design: Theory, Methods and Applications; Kubinyi, E., Ed.; ESCOM, 1993.

7. An Application of 3D-QSAR to the Analysis of the Sequence Specificity of DNA Alkylation by Uracil Mustard. A.M. Doweyko and W.B. Mattes Biochemistry, 1992, 31, 9388.

8. Antiulcer Agents 6. Analysis of the in vitro Biochemical and in vivo Gastric Antisecretory Activity of Substituted Imidazo[1,2-a]pyridines and Related Analogues Using Comparative Molecular Field Analysis and Hypothetical Active Site Lattice (HASL) Methodologies. J.J. Kaminski and A.M. Doweyko J. Med. Chem. 1997, 40, 427-436.

Trademark Acknowledgements and Disclaimers