Phase Brochure - ISP

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The Advantages of Pharmacophore ModelingAs researchers continue to search for new targets of therapeutic interest,transmembrane and G-protein coupled receptors are of ever-increasing importance.However, crystal structures for these targets may be impossible to resolve, posing greatchallenges in rational drug design. Structure-based virtual screening is not an optionwhen the active site geometry is unknown, but assaying an entire library for hits is aninefficient and expensive proposition.Selective serotonin reuptake inhibitors (SSRIs) arecolored according to the quality of their alignmentto the Phase hypothesis. Potent ligands align wellto the pharmacophore, which is in good agreementwith published results.Pharmacophore modeling solves this problem by determining the spatial arrangement ofchemical features that confer drug activity toward a target receptor. Having establishedthe chemical space occupied by active ligands, pharmacophore modeling software allowsresearchers to create 3-D structure-activity relationships, screen databases, andgenerate hits without the benefit of a receptor structure.Phase: Maximizing Returns in Lead DiscoverySchrödinger’s Phase is a pharmacophore modeling and database screening programspecifically designed to bring speed, efficiency, and accuracy to lead discovery efforts.Its features include:• Expert levels of control: Phase distinguishes itself from "black box" software byallowing users to exercise precise control over job settings at all steps, includingpharmacophore scoring, QSAR building, and database screening.The volume of this pharmacophore hypothesis forangiotensin AT 1 antagonists is represented by atranslucent molecular surface. The 6-sitepharmacophore is quickly located using Phase’shigh-dimensional partitioning algorithm.• Universal applicability: While Phase is well suited to drug discovery projects for whichno receptor structure is available, it also allows pharmacophores to be constructed withthe aid of a crystal structure.• Custom feature definitions: Phase locates features using SMARTS pattern matching,making it easy to modify existing feature definitions and to create entirely new customfeatures. Intuitive visualization tools and the rapid location of sites help researchersfine-tune feature definitions.• Excluded volumes: Once a pharmacophore model has been developed, researchersmay define regions of space that are presumed to be occupied by the receptor, andtherefore off-limits to any ligand.• Versatile Database Management: Phase allows researchers to create and save multiconformerdatabases for later screening, or to efficiently generate conformations whilesearching for hits. Researchers can also retrieve hits from a fully prepared database ofcommercially available, druglike compounds that is distributed with the software.• Easy-to-use interface: Phase includes an intuitive step-by-step interface that guidesresearchers through pharmacophore creation, database setup, and database screening.• Cross-platform support: Phase supports Linux and SGI, and features distributedprocessing for all computationally intense job types to expedite large calculations.
Performance-Driven TechnologyPhase equips researchers with novel, highly efficient technology for pharmacophoremodeling:• Thorough conformation generation: Phase uses Schrödinger’s ConfGen technologyto perform systematic explorations about rotatable bonds and calculate associatedconformational energies, retaining only the most reasonable conformations.The hydrophobic contributions to a Phase QSARfor endothelin-A selective antagonists arerepresented here by blue and red cubes, whilecarbon atoms are colored by proximity tovarious pharmacophore features. The quality ofthe Phase hypothesis is confirmed by its abilityto match a diverse set of known actives.• Rapid pharmacophore identification: Phase quickly locates plausiblepharmacophores using a proprietary high-dimensional partitioning algorithm inwhich pharmacophores from different conformations are placed in multi-dimensionalboxes. Each box represents a common pharmacophore only if it contains a sufficientnumber of active ligands.• Advanced pharmacophore scoring: After Phase has located reasonable alignmentsof active ligands, pharmacophores are evaluated according to an open, highlyconfigurable scoring function. Researchers can impose cutoffs to reject unwantedpharmacophores, and enable, disable, and weigh scoring terms as they see fit.• 3-D QSAR: Phase determines how molecular structure affects drug activity bydividing space into a fine cubic grid, encoding atom type occupation as numericalinformation, and performing a partial least-squares (PLS) regression.The bound conformation of PT523, a potent anticancerdrug, is shown as it appears in a crystalstructure (red atoms), and as predicted by the topscoringPhase hypothesis (gray atoms). The Phaseprediction has an RMSD of just 0.78 Å comparedto the crystal structure.• Rapid database screening: Phase employs 2-D and 3-D database keys to efficientlyeliminate molecules that cannot provide hits. Researchers may request partial or fullmatches to a pharmacophore model, emphasize various aspects of matching throughan adjustable fitness measure, apply an excluded volume filter, and predict activityusing a QSAR hypothesis.Accurate pharmacophore modelsTargetDHFRThrombinThermolysinHIV-RTCDK-2TargetDHFRThrombinThermolysinHIV-RTCDK-2Best Phase HypothesisRMSD Rank0.78 Å 12.45 Å 31.40 Å 90.10 Å 30.34 Å 4Best Catalyst HypothesisRMSD Rank1.06 Å 22.27 Å ** 21.96 Å 80.07 Å 181.40 Å 2A pharmacophore is useful only if it accurately represents the arrangement of chemicalfeatures that drive ligand binding. By comparing pharmacophores predicted bymodeling software to those derived from crystal structures, it is possible to gauge aprogram’s ability to reproduce ligand binding modes. In this regard, Phasedemonstrates outstanding performance.In a head-to-head comparison across a previously published test set of fivepharmaceutical targets, Phase generated high-ranking hypotheses that aligned verywell with pharmacophores derived from crystal structures. These results wereuniformly comparable or superior to those produced by Catalyst. For most targets,Phase returned a better alignment to the crystal structures, while Catalyst offeredsignificantly worse performance for HIV-RT and CDK-2.** Catalyst failed to return all pharmacophorefeatures identified in crystal structureSCHRODINGER ®Phase
Page 1: Product ReviewPhasePhaseA high-perf

Phase Brochure - ISP

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