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1.
Bioorg Med Chem Lett ; 19(1): 226-9, 2009 Jan 01.
Article in English | MEDLINE | ID: mdl-19019675

ABSTRACT

An approach and preliminary results for utilizing legacy MEK inhibitors as templates for a reiterative structural based design and synthesis of novel, type III NCKIs (non-classical kinase inhibitors) is described. Evidence is provided that the MEK-pocket or pockets closely related to it may exist in kinases other than MEK.


Subject(s)
Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Catalytic Domain , Drug Design , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology
2.
J Comput Aided Mol Des ; 20(12): 751-62, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17205374

ABSTRACT

In order to develop robust machine-learning or statistical models for predicting biological activity, descriptors that capture the essence of the protein-ligand interaction are required. In the absence of structural information from X-ray or NMR experiments, deriving informative descriptors can be difficult. We have developed feature-map vectors (FMVs), a new class of descriptors based on chemical features, to address this challenge. FMVs, which are derived from the conformational models of a few actives, are low dimensional, problem specific, and highly interpretable. By using shape-based alignments and scoring with chemical features, FMVs can combine information about a molecule's shape and the pharmacophores it can match. In five validation studies, bag classifiers built using FMVs have shown high enrichments for identifying actives for five diverse targets: CDK2, 5-HT(3), DHFR, thrombin, and ACE. The interpretability of these descriptors has been demonstrated for CDK2 and 5-HT(3), where the method automatically discovers the standard literature pharmacophore.


Subject(s)
Drug Design , Algorithms , Artificial Intelligence , Computer Simulation , Computer-Aided Design , Cyclin-Dependent Kinase 2/chemistry , Cyclin-Dependent Kinase 2/drug effects , Humans , In Vitro Techniques , Ligands , Models, Molecular , Proteins/chemistry , Receptors, Serotonin, 5-HT3/chemistry , Receptors, Serotonin, 5-HT3/drug effects
3.
J Med Chem ; 48(9): 3313-8, 2005 May 05.
Article in English | MEDLINE | ID: mdl-15857136

ABSTRACT

Discovering essential features shared by active compounds, an important step in drug-design, is complicated by conformational flexibility. We present a new algorithm to efficiently mine the conformational space of multiple actives and find small subsets of conformations likely to be biologically relevant. The approach identifies chemical and steric similarities between actives, providing insight into features important for binding when structural data are absent. Validation studies (thrombin and CDK2 data) produce alignments similar to protein-based alignments.


Subject(s)
Algorithms , Ligands , Proteins/chemistry , CDC2-CDC28 Kinases/antagonists & inhibitors , CDC2-CDC28 Kinases/chemistry , Crystallography, X-Ray , Cyclin-Dependent Kinase 2 , Models, Molecular , Molecular Conformation , Thrombin/antagonists & inhibitors , Thrombin/chemistry
4.
J Med Chem ; 47(10): 2426-9, 2004 May 06.
Article in English | MEDLINE | ID: mdl-15115386

ABSTRACT

Screening of a computationally designed synthetic library led to the discovery of the N-phenylphenylglycines (NPPGs) as a novel class of human corticotropin releasing factor (h-CRF(1)) antagonists. Several NPPGs with greater potency than the original hit 1 were rapidly identified, and resolution of the racemate demonstrated that only the R-enantiomer displays activity. This structural class represents the first example of a non-peptide CRF(1) antagonist with a stereochemically distinct receptor binding affinity.


Subject(s)
Glycine/analogs & derivatives , Glycine/chemical synthesis , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Combinatorial Chemistry Techniques , Dogs , Drug Design , Glycine/chemistry , Glycine/pharmacokinetics , Humans , Models, Molecular , Molecular Conformation , Stereoisomerism , Structure-Activity Relationship
5.
Curr Opin Drug Discov Devel ; 7(1): 49-61, 2004 Jan.
Article in English | MEDLINE | ID: mdl-14982148

ABSTRACT

This review discusses the current challenges facing researchers developing computational models to predict absorption, distribution, metabolism, excretion and toxicity (ADMET) for early drug discovery. The strengths and weaknesses of different modeling approaches are reviewed and a survey of recent strategies to model several key ADMET parameters, including intestinal permeability, blood-brain barrier penetration, metabolism, bioavailability and drug toxicities, is presented.


Subject(s)
Drug Design , Models, Biological , Models, Molecular , Pharmaceutical Preparations/chemistry , Pharmacokinetics , Potassium Channels, Voltage-Gated , Biological Availability , Biological Transport , Cation Transport Proteins/chemistry , Drug Interactions , Drug-Related Side Effects and Adverse Reactions , Ether-A-Go-Go Potassium Channels , Humans , Pharmaceutical Preparations/metabolism , Potassium Channels/chemistry
6.
Curr Opin Drug Discov Devel ; 6(4): 470-80, 2003 Jul.
Article in English | MEDLINE | ID: mdl-12951810

ABSTRACT

Computational methods are increasingly used to streamline and enhance the lead discovery and optimization process. However, accurate prediction of absorption, distribution, metabolism and excretion (ADME) and adverse drug reactions (ADR) is often difficult, due to the complexity of underlying physiological mechanisms. Modeling approaches have been hampered by the lack of large, robust and standardized training datasets. In an extensive effort to build such a dataset, the BioPrint database was constructed by systematic profiling of nearly all drugs available on the market, as well as numerous reference compounds. The database is composed of several large datasets: compound structures and molecular descriptors, in vitro ADME and pharmacology profiles, and complementary clinical data including therapeutic use information, pharmacokinetics profiles and ADR profiles. These data have allowed the development of computational tools designed to integrate a program of computational chemistry into library design and lead development. Models based on chemical structure are strengthened by in vitro results that can be used as additional compound descriptors to predict complex in vivo endpoints. The BioPrint pharmacoinformatics platform represents a systematic effort to accelerate the process of drug discovery, improve quantitative structure-activity relationships and develop in vitro/in vivo associations. In this review, we will discuss the importance of training set size and diversity in model development, the implementation of linear and neighborhood modeling approaches, and the use of in silico methods to predict potential clinical liabilities.


Subject(s)
Computational Biology/methods , Drug-Related Side Effects and Adverse Reactions , Pharmaceutical Preparations/metabolism , Pharmacokinetics , Animals , Artificial Intelligence , Cytochrome P-450 CYP2D6 Inhibitors , Drug Synergism , Enzyme Inhibitors/pharmacology , Humans , Models, Molecular , Predictive Value of Tests , Quantitative Structure-Activity Relationship
7.
Nat Struct Biol ; 9(8): 582-5, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12134141

ABSTRACT

The streptavidin-biotin system has provided a unique opportunity to investigate the molecular details of ligand dissociation pathways. An underlying mechanistic question is whether ligand dissociation proceeds with a relatively ordered process of bond breaking and ligand escape. Here we report a joint computational and crystallographic study of the earliest events in biotin dissociation. In molecular dynamics potential of mean force simulations, a water molecule from a defined access channel intercalated into the hydrogen bond between Asp 128 and biotin, bridging them and stabilizing an intermediate state. In forced biotin dissociation simulations, this event led to subsequent bond breaking steps and ligand escape. In equilibrium simulations, the water molecule was sometimes observed to move back to the access channel with re-formation of the biotin hydrogen bond. Analysis of streptavidin crystal structures revealed a close overlap of crystallographically defined and simulated waters in the water access channel. These results suggest that biotin dissociation is initiated by stochastic coupling of water entry with lengthening of a specific biotin hydrogen-bonding interaction.


Subject(s)
Biotin/chemistry , Streptavidin/chemistry , Aspartic Acid/chemistry , Binding Sites , Biotin/metabolism , Crystallography, X-Ray , Hydrogen Bonding , In Vitro Techniques , Ligands , Macromolecular Substances , Models, Molecular , Streptavidin/metabolism , Thermodynamics , Water/chemistry
8.
J Med Chem ; 45(9): 1737-40, 2002 Apr 25.
Article in English | MEDLINE | ID: mdl-11960484

ABSTRACT

P-glycoprotein (P-gp) functions as a drug efflux pump, mediating multidrug resistance and limiting the efficacy of many drugs. Clearly, identification of potential P-gp substrate liability early in the drug discovery process would be advantageous. We describe a multiple-pharmacophore model that can discriminate between substrates and nonsubstrates of P-gp with an accuracy of 63%. The application of this filter allows large virtual libraries to be screened efficiently for compounds less likely to be transported by P-gp.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/chemistry , Databases, Factual , Models, Molecular , Combinatorial Chemistry Techniques , Hydrogen Bonding , Indinavir/chemistry , Molecular Conformation , Nicardipine/chemistry
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