Ligand-based design techniques use information about one or several known actives (ligands) as a basis for the design of lead compounds. It includes applications to address critical ligand-based design tasks, such as structure-activity relationship modeling, pharmacophore hypothesis generation, molecular alignment, and ADME prediction. A ligand's shape is its most significant property. There are no poorly fitting, high-affinity ligands. Shape matters. If the three dimensional coordinates of a ligand are known, whether from experiment or rational analysis or can be easily derived due to limited conformational flexibility (or inspired guesswork), the problem of finding a molecule of similar activity is simplified. OpenEye approach is to define shape as a rigorous metric property and search vast conformational expansions for similar structures. Others select points in space (pharmacophores, the Cresset field points) that must be matched, or generate partial descriptions of shapes from fragments (Cramer's topomer method). Not surprisingly, these all work to some degree or other because molecular interactions occur in three dimensions, not via strings.

ROCS- chemical similarity analysis via rapid 3D molecular shape searches

ROCS, a industry leading shape-matching product, allows for fast comparisons of shape, followed by simple matching of chemical functionalities. ROCS shapes to be defined either by molecule or by grid, capable of distributing searches over networks of computers. ROCS has never been heard of failing. It is often so successful at finding interesting leads, physical screens have been cancelled. ROCS results are easy to visualize and comprehend and has been widely adopted by medicinal chemists.

Seascape Scientific Partner:OpenEye Scientific Software, New Mexico

EON- chemical similarity analysis via comparison of electrostatics overlay

Given an alignment of two molecules, EON calculates and compares their electrostatic fields. It can also perform terminal rotor adjustments that do little to change the shape match but that can dramatically alter the electrostatic profile. EON has been used to design higher-affinity ligands (from a virtual screen) and also as a method of bio-isostere identification.

Seascape Scientific Partner:OpenEye Scientific Software, New Mexico

BROOD- bioisostere identification using shape, chemistry and electrostatic similarity

Bioisosteric replacement is a technique used by medicinal chemists to modify the physical or biological properties of lead molecules without deleteriously affecting their activity. Brood uses the shape, chemistry and electrostatic similarity technology it shares with ROCS and EON to compare molecular fragments and identify bioisosteres of a query fragment. Brood is packaged with two pre-generated multiconformer databases of molecular fragment that are ready for searching. In addition, it provides methods for fragmenting molecular databases using a default or user provided fragmentation scheme. Brood can search more than 250,000 molecular fragments per hour, allowing examination of common fragments in minutes and query of larger more complex databases in a few hours.

Seascape Scientific Partner:OpenEye Scientific Software, New Mexico

QUACPAC- quality charge states and charges for small molecules and proteins

Calculating the correct partial charge distribution for a compound is essential if one wishes accurate electrostatic fields or other electrostatic quantities. One set of methods use electro-negativity to apportion charge around a molecule. Force-fields such as MMFF use this method and OpenEye has implemented such. Better physical agreement, however, can be found by the Bayly method, AM1-BCC. Here, an initial AM1 calculation is 'corrected' by bond-types such that very high quality (essentially ab initio level) can be obtained very rapidly (~1/s).

Seascape Scientific Partner:OpenEye Scientific Software, New Mexico

WABE- electrostatics optimization of a lead compound

If you know the shape is right, what about better electrostatics? WABE is a method and approach to maintain a similar shape and to experiment with different electrostatic potentials. Given a potential distribution of an active compound and a second molecule with the same shape but different chemical graph, WABE will generate analogs by a series of isosteric replacements. WABE is capable of generating anywhere from 10 to 10,000,000 potential leads, depending on the rules of replacement, which are 'learnt' from chemistries presented to it. Because the shape remains the same the potential comparison with the active molecule can be made instantaneously (~100,000 per second).

Seascape Scientific Partner:OpenEye Scientific Software, New Mexico

VIDA II - molecular visualization and data analysis on very large datasets

Many of OpenEye tools either generate or sift through vast quantities of 3D ligand information, and as such VIDA II is the best program available for large scale visualization. VIDA II can handle small lists of molecules or corporate collections and can view them as multi-pane 3D, 2D depictions, SMILES strings, spreadsheet entries, html forms, graphs and drill-down lists. It can view them in the context of proteins or other small molecules, as simple line models or photo-realistic balls and sticks. With a python core VIDA II is easily scriptable and can be tailored to many end-uses. Works, naturally, on many platforms.

Seascape Scientific Partner:OpenEye Scientific Software, New Mexico

4D-QSAR - Quantitative 3D Pharmacophore Models of Biopotency

4D-QSAR analysis incorporates the conformational, alignment, and pharmacophore degrees of freedom in the development of 3D-QSAR models. It is used to create and screen against 3D-pharmacophore QSAR models and can be used in receptor-independent or receptor-dependent modes.

4D-QSAR can be used as follows:

  • As a CoMFA pre-processor to provide conformations and alignments
  • In combination with CoMFA to combine the field descriptors of CoMFA with the GCOD descriptors of 4D-QSAR to build a "best" model, or
  • In addition CoMFA because it treats multiple alignments, conformations and embedded pharmacophores which are CoMFA limitations.

The 4D-QSAR process:

  • Model the 3D-pharmacophore
  • View the active conformation
  • Screen compounds using 4D-QSAR model

Seascape Scientific Partner: Chem21/Dr. Anton Hopfinger of Univ. of Illinois.

ADMET/MI-QSAR - Predict Performance Profiles of Drug Candidates

ADMET/MI-QSAR permits the estimation of a wide range of ADME and toxicity endpoints based on the interaction of test compounds with models of cellular membranes and a set of unique property descriptors.

ADMET properties are modeled based on molecular interactions between test compounds and cell membranes.

Quantitative structure-activity relationship (QSAR) analysis relates the magnitude of a property exhibited by a molecule to its physicochemical and structural parameters. Many ADMET features are related to how the molecule interacts with biological membranes. Some toxicity endpoints, such as skin and eve irritations, also depend on membrane interactions. As part of the QSAR model-building process, the ADMET/MI-QSAR method takes these interactions into account to treat the largest possible range of ADMET biopharmaceutical and toxicology problems.

Seascape Scientific Partner: Chem21/Dr. Anton Hopfinger of Univ. of Illinois




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