the Hypothetical Active Site Lattice

A Method for 3D-QSAR

HASL 4.00S for Sybyl Now Available! Click here for more information

Since the introduction of HASL in 1988 (J. Med. Chem. 1988, 31, 1396) this 3D-QSAR methodology has been extensively tested and successfully applied in a wide variety of structure-activity investigations:


Details of the HASL modeling paradigm can be found in recent reviews of 3D-QSAR approaches:

  • HASL modeling is accomplished through the intermediate conversion of a molecule to a set of regularly-spaced points (lattice) defined by Cartesian coordinates (x,y,z) and atom type. In this way individual molecules can be compared to one another, and their lattices merged to form a composite description called the HASL.

  • The activity (ED50, pKi, etc.) of each molecule is distributed among the points in the HASL in such a way that the sum of the partial activity values associated with a set of points belonging to each molecule is equal to the activity for that molecule.

  • The result is a model of the active (receptor) site consisting of points in space capable of predicting the activities of as yet untested molecules. A recent innovation, the construction of a predictive 3D-pharmacophore, is based on the selective editing of a HASL model.

  • Recent investigations have shown that HASL modeling of data sets previously analyzed using the popular 3D-QSAR technique, CoMFA (Tripos, Inc.), has resulted in similar degrees of predictivity and insight into active site binding. This observation is not unsurprising, since CoMFA, like HASL, relies on the deconvolution of a complex 3D problem into equidistant points in space. While CoMFA examines the effects (steric and electrostatic) outside the molecule, HASL focusses on a heuristic inspection of atom types within the Van der Waal's domain of the molecule.

    The new Sybyl-interfaced version of HASL has several innovative features that take unique advantage of the power of Sybyl to create HASL models and graphically examine the model results. HASL4.0S includes an expanded parameter set that allows two values per atom type, a new cross-validation routine, interfaces to HINT and Molconn-Z, and new map contouring algorithms that provide a novel and informative view of the HASL model results.

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