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SQ: a program for rapidly producing pharmacophorically relevent molecular superpositions
M D Miller1, R P Sheridan, S K Kearsley
1Department of Molecular Systems, Merck Research Laboratories, Sumneytown Pike, West Point, Pennsylvania 19486, USA.
Journal of Medicinal Chemistry
|May 7, 1999
Summary
A new method, SQ, offers fast, automatic 3D molecular alignment for drug discovery. It accurately ranks compounds by similarity, improving chemical screening and identifying diverse molecules with similar biological activity.
Area of Science:
- Computational chemistry
- Cheminformatics
- Drug discovery
Background:
- Accurate 3D molecular alignment is crucial for understanding drug-receptor interactions and for virtual screening.
- Existing methods may lack speed, objectivity, or the ability to recognize pharmacologically relevant properties.
Purpose of the Study:
- To introduce and validate SQ, a novel computational method for fast, automatic, and objective 3D molecular alignment.
- To demonstrate SQ's utility in assessing molecular similarity and ranking compounds for chemical screening.
- To showcase SQ's capability in identifying structurally diverse compounds with similar biological activities.
Main Methods:
- SQ employs an atom-based clique-matching algorithm followed by a scoring function parameterized for pharmacologically relevant atomic properties.
- The method was validated using six receptor-ligand complexes from the Brookhaven Protein Data Bank.
- SQ was used to screen the MDDR database against three known inhibitors (thrombin, HIV protease, angiotensin II) using precomputed conformations.
Main Results:
- SQ alignments of isolated ligands correlated well with alignments of ligands within superimposed receptors.
- SQ demonstrated superior performance compared to its predecessor, SEAL.
- SQ successfully identified compounds with similar biological activities to the probe molecules from a large chemical database.
- The SQ score effectively ranked candidate molecules based on 3D similarity.
Conclusions:
- SQ provides a fast, automatic, and objective approach to 3D molecular alignment, outperforming previous methods.
- SQ is a valuable tool for virtual screening, enabling efficient ranking and selection of potential drug candidates.
- SQ can identify topologically diverse compounds with shared pharmacological relevance, aiding in the discovery of novel therapeutics.