We present the first receptor-based pharmacophore model for HIV-1 integrase. The development of "dynamic" pharmacophore models is a new method that accounts for the inherent flexibility of the active site and aims to reduce the entropic penalties associated with binding a ligand. Furthermore, this new drug discovery method overcomes the limitation of an incomplete crystal structure of the targe...

In an effort to develop a quantitative ligand-binding model for the receptor tyrosine kinases, a pharmacophore search was first used to identify structural features that are common in two novel sets of 12 molecules of the 3-substituted indolin-2-ones and 19 compounds of the benzylidene malononitriles with low-to-high affinity for HER2, a kind of receptor tyrosine kinase. The common pharmacophor...

A major goal in contemporary drug design is to develop new ligands with high affinity of binding toward a given protein receptor. Pharmacophore, which is the three-dimensional arrangement of essential features that enable a molecule to exert a particular biological effect, is a very useful model for achieving this goal. If the three dimensional structure of the receptor is known, pharmacophore ...

To design new chemotypes with enhanced potencies against the HIV integrase enzyme, 3D pharmacophore models were generated and QSAR study was carried out on 44 novel indole b-diketo acid derivatives and coumarin-based Inhibitors. A five-point pharmacophore with two hydrogen bond acceptors (A) and three aromatic rings (R) as pharmacophore features was developed by PHASE module of Schrodinger suit...

Pharmacophore models play an essential role in drug discovery. Generating pharmacophore models which encode accurate molecular recognition features are highly dependent on properly defined annotations. Simplistic or ill-defined pharmacophore annotations which do not capture subtle electronic or geometric effects lead to many inaccuracies. SMARTS patterns which are often used to specify annotati...

A neurokinin 2 (NK2) antagonist pharmacophore model has been developed on the basis of five non-peptide antagonists from several structurally diverse classes. To evaluate the pharmacophore model, another 20 antagonists were fitted to the model. By use of exhaustive conformational analysis (MMFFs force field and the GB/SA hydration model) and least-squares molecular superimposition studies, 23 o...

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The aim of this study was to use a combined structure and pharmacophore modeling approach to extract information regarding dopamine D₁ receptor agonism and D₁/D₂ agonist selectivity. A 3D structure model of the D₁ receptor in its agonist-bound state was constructed with a full D₁ agonist present in the binding site. Two different binding modes were identified using (+)-doxanthrine or SKF89626 i...

We describe a novel method to develop energetically optimized, structure-based pharmacophores for use in rapid in silico screening. The method combines pharmacophore perception and database screening with protein ligand energetic terms computed by the Glide XP scoring function to rank the importance of pharmacophore features. We derive energy-optimized pharmacophore hypotheses for 30 pharmaceut...

Neuronal nitric oxide synthase (nNOS) plays an important role in neurotransmission and smooth muscle relaxation. Selective inhibition of nNOS over its other isozymes is highly desirable for the treatment of neurodegenerative diseases to avoid undesirable effects. In this study, we present a workflow for the identification and prioritization of compounds as potentially selective human nNOS inhib...