Schrödinger - Phase: A high-performance program for ligand-based drug design

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The bound conformation of PT523, a potent anticancer drug, is shown as it appears in a crystal structure (red atoms), and as predicted by the topscoring Phase hypothesis (gray atoms). The Phase prediction has an RMSD of just 0.78 Å compared to the crystal structure.

Phase: A high-performance program for ligand-based drug design

Phase is a complete package of pharmacophore modeling tools that offers scientists an unparalleled level of control at each step. Fast, accurate, and highly configurable, Phase is a powerful tool for hit generation and lead hopping.

The Advantages of Pharmacophore Modeling

As 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 great challenges in rational drug design. Structure-based virtual screening is not an option when the active site geometry is unknown, but assaying an entire library for hits is an inefficient and expensive proposition.

Pharmacophore modeling solves this problem by determining the spatial arrangement of chemical features that confer drug activity toward a target receptor. Having established the chemical space occupied by active ligands, pharmacophore modeling software allows researchers to create 3D structure-activity relationships, screen databases, and generate hits without the benefit of a receptor structure.

Works to Cite

Dixon, S. L.; Smondyrev, A. M.; Knoll, E. H.; Rao, S. N.; Shaw, D. E.; Friesner, R. A., "PHASE: A New Engine for Pharmacophore Perception, 3D QSAR Model Development, and 3D Database Screening. 1. Methodology and Preliminary Results," J. Comput. Aided Mol. Des., 2006, 20, 647-671.

Dixon, S. L.; Smondyrev, A. M.; Rao, S. N., "PHASE: A Novel Approach to Pharmacophore Modeling and 3D Database Searching," Chem. Biol. Drug Des., 2006, 67, 370-372.

Features

Shape-based Screening: Phase Shape provides a standalone module for rapid shape-based screening. Screen hundreds of molecules per second using either a pre-generated conformer database or generate conformers on-the-fly. The graphical interface allows for easy job submission along with extensive control of options, such as atom-typing schemes, excluded volumes, and custom atom weighting.

Expert levels of control: Phase distinguishes itself from "black box" software by allowing users to exercise precise control over job settings at all steps, including pharmacophore scoring, QSAR building, and database screening.

Universal applicability: While Phase is well suited to drug discovery projects for which no receptor structure is available, it also allows pharmacophores to be constructed with the 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 custom features. Intuitive visualization tools and the rapid location of sites help researchers fine-tune feature definitions.

Excluded volumes: Once a pharmacophore model has been developed, researchers may define regions of space that are presumed to be occupied by the receptor, and therefore off-limits to any ligand.

Efficient database management: Phase uses Schrödinger's ConfGen for extremely rapid and thorough sampling of conformational space, and allows researchers to simultaneously create a 3D database from a structure library while searching it for hits.

A fully prepared database of purchasable compounds: Schrödinger offers the Phase Commercially Available Compound Database (CACDB), against which a pharmacophore model can be screened for hit generation.