Pruned receptor surface models and pharmacophores for three-dimensional database searching

Journal of Medicinal Chemistry
Jeffrey J SutherlandDonald F Weaver

Abstract

A pharmacophore represents the 3D arrangement of chemical features that are shared by molecules exhibiting activity at a protein receptor. Pharmacophores are routinely used in 3D database searching for identifying potential lead compounds. The lack of shape constraints causes the query to identify compounds that could not fit into the active site. In the absence of structural information, a receptor surface model (RSM) can be used to represent the active site. The RSM consists of a surface that envelops a set of known actives after these have been aligned using their common features. When used for database searching, a RSM is overconstraining as it restricts access to regions that could be occupied by ligands, such as the solvent-protein interface or unexplored pockets. We describe a protocol for developing pruned RSMs using information gleaned from 3D quantitative structure-activity relationship (QSAR) models. We examined the performance of queries that consist of pharmacophores used alone or with pruned or unpruned RSMs by performing searches on six databases containing known actives distributed among inactives. The pruned RSMs yield an average selectivity 1.8 times greater than that for pharmacophore queries, compared to 1.6...Continue Reading

References

Apr 1, 1987·Journal of Computer-aided Molecular Design·D MayerG R Marshall
Aug 5, 1994·Journal of Medicinal Chemistry·D E Walters, R M Hinds
Oct 20, 1998·Journal of Computer-aided Molecular Design·J BoströmT Liljefors
Jan 8, 1999·Journal of Computer-aided Molecular Design·M ViethC L Brooks
Jan 15, 1999·Journal of Medicinal Chemistry·J MountA N Jain
Mar 25, 2000·European Journal of Medicinal Chemistry·A GolbraikhJ R Chrétien
Apr 11, 2000·Journal of Computer-aided Molecular Design·C Lemmen, T Lengauer
May 29, 2001·Current Pharmaceutical Design·J S MasonE J Martin
Oct 18, 2001·Journal of Chemical Information and Computer Sciences·T I OpreaP D Leeson
Mar 22, 2002·Journal of Medicinal Chemistry·Albert PalomerAntonio Espinosa
May 31, 2002·Journal of Medicinal Chemistry·Jayashree SrinivasanRobert V Stanton
Oct 16, 2002·Journal of Chemical Information and Computer Sciences·Evan A HeckerDavid J Diller
Feb 27, 2003·Journal of Computer-aided Molecular Design·Yogendra PatelAndrew R Leach
Mar 21, 2003·Medicinal Research Reviews·Ingo Muegge
Jul 23, 2003·Current Pharmaceutical Design·John H van Drie
Aug 1, 1988·Journal of the American Chemical Society·R D CramerJ D Bunce

❮ Previous
Next ❯

Citations

Aug 4, 2012·Journal of Chemical Information and Modeling·Yunierkis Pérez-CastilloAnn Nowé
Jan 1, 2009·Journal of Cheminformatics·Robert D Clark
Aug 24, 2010·Journal of Computational Chemistry·Ahmed Mutanabbi AbdulaMutasem O Taha

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.