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    NEWLEAD

    Vincenzo Tschinke

    Novartis Pharma AG (formerly)

    N. Claude Cohen

    Synergix Ltd.

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    Abstract

    NEWLEAD [1] is a computer program for the automatic

    generation of candidate structures. The input for the program

    is a set of fragments in the three-dimensional orientation

    corresponding to a given pharmacophore model. The treatment

    consists in connecting the fragments with spacers assembled

    from small chemical entities (atoms, chains or ring moieties).

    The results are new structures containing the fragments in

    the orientation defined in the input. The program offers

    the opportunity of rapidly applying a pharmacophore model

    in drug-design by generating automatically a set of chemical

    sructures conforming to the model.

    We have tested [1] the program on several sets of input fragments,

    each comprising selected functional groups obtained from the

    bio-active conformations of reference molecules available from

    the literature. In addition to the expected solutions, the

    program can generate new structures that are chemically

    unrelated to the reference molecules. This provides an

    unbiased starting point for the design of new generations

    of lead structures. The treatment is very fast, because only

    a few bonds are created between building blocks already having

    ideal geometries.

    The user should define the input fragments based on a valid

    pharmacophore. A library of spacers to connect the fragments

    is provided with the software. The user can partly influence

    the outcome of a program run by defining preferred connection

    points, geometric parameters and types of atoms for the

    connections. The output results are clustered based on the

    similarity of the connecting spacers.

    The ability to generate rapidly a variety of molecules

    conforming to a three-dimensional pharmacophore model

    makes NEWLEAD a useful tool with wide applicability in

    rational drug design, including the areas of molecular

    mimicry and peptidomimetism.

[1] Tschinke, V.; Cohen N.C. The NEWLEAD Program: A New Method

    for the Design of Candidate Structures from Pharmacophoric

    Hypotheses. J. Med.Chem. 1993, 36, 3863-3870.

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    Instructions

 a) To extract the data, place the file 'newlead_linux.tar.gz' in

    a convenient directory, then decompress it:

    gzip -dc newlead_linux.tar.gz > newlead_linux.tar

    tar xvf newlead_linux.tar

 b) To install the program, follow the instructions in the

    file 'NEWLEAD_README'

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