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1.
Drug Metab Dispos ; 48(6): 521-527, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32234735

RESUMO

Two novel homodimer metabolites were identified in rat samples collected during the in vivo study of GDC-0994. In this study, we investigated the mechanism of the formation of these metabolites. We generated and isolated the dimer metabolites using a biomimetic oxidation system for NMR structure elucidation to identify a symmetric dimer formed via carbon-carbon bond between two pyrazoles and an asymmetric dimer formed via an aminopyrazole-nitrogen to pyrazole-carbon bond. In vitro experiments demonstrated formation of these dimers was catalyzed by cytochrome P450 enzymes (P450s) with CYP3A4/5 being the most efficient. Using density functional theory, we determined these metabolites share a mechanism of formation, initiated by an N-H hydrogen atom abstraction by the catalytically active iron-oxo of P450s. Molecular modeling studies also show these dimer metabolites fit in the CYP3A4 binding site in low energy conformations with minimal protein rearrangement. Collectively, the results of these experiments suggest that formation of these two homodimer metabolites is mediated by CYP3A, likely involving activation of two GDC-0994 molecules by a single P450 enzyme and proceeding through a radical coupling mechanism. SIGNIFICANCE STATEMENT: These studies identified structures and enzymology for two distinct homodimer metabolites and indicate a novel biotransformation reaction mediated by CYP3A. In it, two molecules may bind within the active site and combine through radical coupling. The mechanism of dimerization was elucidated using density functional theory computations and supported by molecular modeling.

2.
J Chem Inf Model ; 54(2): 462-9, 2014 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-24432790

RESUMO

Water is the natural medium of molecules in the cell and plays an important role in protein structure, function and interaction with small molecule ligands. However, the widely used molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) method for binding energy calculation does not explicitly take account of water molecules that mediate key protein-ligand interactions. We have developed a protocol to include water molecules that mediate ligand-protein interactions as part of the protein structure in calculation of MM/PBSA binding energies (a method we refer to as water-MM/PBSA) for a series of JNK3 kinase inhibitors. Improved correlation between water-MM/PBSA binding energies and experimental IC50 values was obtained compared to that obtained from classical MM/PBSA binding energy. This improved correlation was further validated using sets of neuraminidase and avidin inhibitors. The observed improvement, however, appears to be limited to systems in which there are water-mediated ligand-protein hydrogen bond interactions. We conclude that the water-MM/PBSA method performs better than classical MM/PBSA in predicting binding affinities when water molecules play a direct role in mediating ligand-protein hydrogen bond interactions.


Assuntos
Proteína Quinase 10 Ativada por Mitógeno/química , Simulação de Dinâmica Molecular , Água/química , Ligantes , Proteína Quinase 10 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 10 Ativada por Mitógeno/metabolismo , Ligação Proteica , Conformação Proteica , Inibidores de Proteínas Quinases/farmacologia , Termodinâmica
3.
Biochem Biophys Res Commun ; 441(2): 291-6, 2013 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-24070613

RESUMO

Alzheimer's disease (AD) is a devastating neurodegenerative disease affecting millions of people. ß-Secretase-1 (BACE-1), an enzyme involved in the processing of the amyloid precursor protein (APP) to form Aß, is a well validated target for AD. Herein, the authors characterize 10 randomly selected hydroxyethylamine (HEA) BACE-1 inhibitors in terms of their association and dissociation rate constants and thermodynamics of binding using surface plasmon resonance (SPR). Rate constants of association (ka) measured at 25 °C ranged from a low of 2.42×10(4) M(-1) s(-1) to the highest value of 8.3×10(5) M(-1) s(-1). Rate constants of dissociation (kd) ranged from 1.09×10(-4) s(-1) (corresponding to a residence time of close to three hours), to the fastest of 0.028 s(-1). Three compounds were selected for further thermodynamic analysis where it was shown that equilibrium binding was enthalpy driven while unfavorable entropy of binding was observed. Structural analysis revealed that upon ligand binding, the BACE-1flap folds down over the bound ligand causing an induced fit. The maximal difference between alpha carbon positions in the open and closed conformations of the flap was over 5 Å. Thus the negative entropy of binding determined using SPR analysis was consistent with an induced fit observed by structural analysis.


Assuntos
Doença de Alzheimer/enzimologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Etanolaminas , Inibidores de Proteases/farmacologia , Secretases da Proteína Precursora do Amiloide/química , Ácido Aspártico Endopeptidases/química , Ácido Aspártico Proteases/antagonistas & inibidores , Ácido Aspártico Proteases/química , Enzimas Imobilizadas/antagonistas & inibidores , Enzimas Imobilizadas/química , Humanos , Cinética , Inibidores de Proteases/química , Conformação Proteica , Termodinâmica
4.
J Chem Inf Model ; 53(8): 2065-72, 2013 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-23845109

RESUMO

Does a single molecular trajectory provide an adequate sample conformational space? Our calculations indicate that for Molecular Mechanics--Poisson-Boltzmann Surface Area (MM-PBSA) measurement of protein ligand binding, a single molecular dynamics trajectory does not provide a representative sampling of phase space. For a single trajectory, the binding energy obtained by averaging over a number of molecular dynamics frames in an equilibrated system will converge after an adequate simulation time. A separate trajectory with nearly identical starting coordinates (1% randomly perturbed by 0.001 Å), however, can lead to a significantly different calculated binding energy. Thus, even though the calculated energy converges for a single molecular dynamics run, the variation across separate runs implies that a single run inadequately samples the system. The divergence in the trajectories is reflected in the individual energy components, such as the van der Waals and the electrostatics terms. These results indicate that the trajectories sample different conformations that are not in rapid exchange. Extending the length of the dynamics simulation does not resolve the energy differences observed between different trajectories. By averaging over multiple simulations, each with a nearly equivalent starting structure, we find the standard deviation in the calculated binding energy to be ∼1.3 kcal/mol. The work presented here indicates that combining MM-PBSA with multiple samples of the initial starting coordinates will produce more precise and accurate estimates of protein/ligand affinity.


Assuntos
Simulação de Dinâmica Molecular , Proteínas/química , Proteínas/metabolismo , Ligantes , Dinâmica não Linear , Distribuição de Poisson , Ligação Proteica , Conformação Proteica , Reprodutibilidade dos Testes , Temperatura , Termodinâmica
5.
PLoS One ; 8(7): e66879, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23861750

RESUMO

Surface Plasmon Resonance (SPR) is rarely used as a primary High-throughput Screening (HTS) tool in fragment-based approaches. With SPR instruments becoming increasingly high-throughput it is now possible to use SPR as a primary tool for fragment finding. SPR becomes, therefore, a valuable tool in the screening of difficult targets such as the ubiquitin E3 ligase Parkin. As a prerequisite for the screen, a large number of SPR tests were performed to characterize and validate the active form of Parkin. A set of compounds was designed and used to define optimal SPR assay conditions for this fragment screen. Using these conditions, more than 5000 pre-selected fragments from our in-house library were screened for binding to Parkin. Additionally, all fragments were simultaneously screened for binding to two off target proteins to exclude promiscuous binding compounds. A low hit rate was observed that is in line with hit rates usually obtained by other HTS screening assays. All hits were further tested in dose responses on the target protein by SPR for confirmation before channeling the hits into Nuclear Magnetic Resonance (NMR) and other hit-confirmation assays.


Assuntos
Ensaios de Triagem em Larga Escala , Fragmentos de Peptídeos/química , Ressonância de Plasmônio de Superfície , Ubiquitina-Proteína Ligases/química , Ditiotreitol/química , Ditiotreitol/metabolismo , Descoberta de Drogas , Ensaios de Triagem em Larga Escala/métodos , Cinética , Ligantes , Ressonância Magnética Nuclear Biomolecular , Fragmentos de Peptídeos/metabolismo , Ligação Proteica , Substâncias Redutoras/química , Substâncias Redutoras/metabolismo , Ressonância de Plasmônio de Superfície/métodos , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ubiquitina-Proteína Ligases/metabolismo
6.
ChemMedChem ; 8(8): 1295-313, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23794260

RESUMO

Polo-like kinase-2 (Plk-2) has been implicated as the dominant kinase involved in the phosphorylation of α-synuclein in Lewy bodies, which are one of the hallmarks of Parkinson's disease neuropathology. Potent, selective, brain-penetrant inhibitors of Plk-2 were obtained from a structure-guided drug discovery approach driven by the first reported Plk-2-inhibitor complexes. The best of these compounds showed excellent isoform and kinome-wide selectivity, with physicochemical properties sufficient to interrogate the role of Plk-2 inhibition in vivo. One such compound significantly decreased phosphorylation of α-synuclein in rat brain upon oral administration and represents a useful probe for future studies of this therapeutic avenue toward the potential treatment of Parkinson's disease.


Assuntos
Encéfalo/metabolismo , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , alfa-Sinucleína/metabolismo , Animais , Sítios de Ligação , Barreira Hematoencefálica/metabolismo , Feminino , Células HEK293 , Meia-Vida , Humanos , Masculino , Camundongos , Simulação de Dinâmica Molecular , Fosforilação/efeitos dos fármacos , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Estrutura Terciária de Proteína , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Ratos Sprague-Dawley
8.
Bioorg Med Chem Lett ; 23(7): 2181-6, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-23465612

RESUMO

The structure-activity relationship of a series of dihydroisoquinoline BACE-1 inhibitors is described. Application of structure-based design to screening hit 1 yielded sub-micromolar inhibitors. Replacement of the carboxylic acid of 1 was guided by X-ray crystallography, which allowed the replacement of a key water-mediated hydrogen bond. This work culminated in compounds such as 31, which possess good BACE-1 potency, excellent permeability and a low P-gp efflux ratio.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico/química , Desenho de Fármacos , Isoquinolinas/farmacologia , Inibidores de Proteases/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Catálise , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Isoquinolinas/síntese química , Isoquinolinas/química , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Relação Estrutura-Atividade
9.
Bioorg Med Chem Lett ; 23(9): 2743-9, 2013 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-23522834

RESUMO

Polo-like kinase-2 (Plk-2) is a potential therapeutic target for Parkinson's disease and this Letter describes the SAR of a series of dihydropteridinone based Plk-2 inhibitors. By optimizing both the N-8 substituent and the biaryl region of the inhibitors we obtained single digit nanomolar compounds such as 37 with excellent selectivity for Plk-2 over Plk-1. When dosed orally in rats, compound 37 demonstrated a 41-45% reduction of pS129-α-synuclein levels in the cerebral cortex.


Assuntos
Desenho de Fármacos , Inibidores de Proteínas Quinases/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Administração Oral , Animais , Encéfalo/metabolismo , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Células HEK293 , Meia-Vida , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , Pteridinas/síntese química , Pteridinas/química , Pteridinas/farmacocinética , Ratos , Relação Estrutura-Atividade
10.
Invest New Drugs ; 31(3): 576-86, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23179338

RESUMO

Deletions or mutations in the tumor suppressor gene DPC4 (deleted in pancreatic carcinoma locus 4) are common in colon and pancreatic cancers. Using the Target-related Affinity Profiling (TRAP) chemical library screening method, a novel agent, UA8967, was selected for further studies because it showed greater potency in DPC4-deleted HCT-116 colon cancer cells. Cytotoxicity studies in six pancreatic cancer cell lines (MiaPaca-2, Panc-1, BxPC3, CF-PAC1, AsPC1, and T3M4), one normal human pancreatic ductal epithelial line (HPDE-6) and the HCT-116 DPC4(+/+) and HCT-116 DPC4(-/-) colon cancer cells showed IC50s ranging from 12-61 µM for exposure times of 72 h. Analysis of schedule dependence showed no advantage for long drug exposure times. There was also no selective inhibition of DNA, RNA or protein synthesis after exposure to UA8967. At 24-48 h, there was an accumulation of cells in G0/G1-phase and a proportionate reduction in S-phase cells. Within 1-6 h of exposure, cells were found to undergo an autophagic response, followed at 24 h by a low level of caspase-independent apoptosis with some necrosis. Because of the relatively non-specific mechanistic effects of UA8967, plasma membrane viability was evaluated using uptake of trypan blue and Sytox® Green dyes, and leakage of LDH. There was a dose dependent increase in Sytox® Green staining, trypan blue uptake and LDH leakage with increasing concentrations of UA8967, suggesting that UA8967 is affecting the plasma membrane. The DPC4(-/-) cells were more sensitive to UA8967 but not to DMSO, suggesting a drug-specific effect on cell membrane integrity.


Assuntos
Antineoplásicos/farmacologia , Indóis/farmacologia , Piperazinas/farmacologia , Proteína Smad4/genética , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , L-Lactato Desidrogenase/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos
11.
J Med Chem ; 54(15): 5403-13, 2011 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-21692479

RESUMO

The metabolism of poly(ADP-ribose) (PAR) in response to DNA strand breaks, which involves the concerted activities of poly(ADP-ribose) polymerases (PARPs) and poly(ADP-ribose) glycohydrolase (PARG), modulates cell recovery or cell death depending upon the level of DNA damage. While PARP inhibitors show high promise in clinical trials because of their low toxicity and selectivity for BRCA related cancers, evaluation of the therapeutic potential of PARG is limited by the lack of well-validated cell permeable inhibitors. In this study, target-related affinity profiling (TRAP), an alternative to high-throughput screening, was used to identify a number of druglike compounds from several chemical classes that demonstrated PARG inhibition in the low-micromolar range. A number of analogues of one of the most active chemotypes were synthesized to explore the structure-activity relationship (SAR) for that series. This led to the discovery of a putative pharmacophore for PARG inhibition that contains a modified salicylanilide structure. Interestingly, these compounds also inhibit PARP-1, indicating strong homology in the active sites of PARG and PARP-1 and raising a new challenge for development of PARG specific inhibitors. The cellular activity of a lead inhibitor was demonstrated by the inhibition of both PARP and PARG activity in squamous cell carcinoma cells, although preferential inhibition of PARG relative to PARP was observed. The ability of inhibitors to modulate PAR metabolism via simultaneous effects on PARPs and PARG may represent a new approach for therapeutic development.


Assuntos
Inibidores Enzimáticos/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Salicilanilidas/farmacologia , Carcinoma de Células Escamosas/metabolismo , Inibidores Enzimáticos/síntese química , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases , Salicilanilidas/síntese química , Relação Estrutura-Atividade
12.
Curr Top Med Chem ; 7(15): 1514-24, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17897038

RESUMO

We review recent advances in computer modeling of molecular shape in drug discovery. We summarize the ways of representing shape computationally, discuss the various means of aligning molecules and shapes, consider the various ways of scoring similarity of shapes, and describe the ways in which these shapes can be used to construct molecular descriptors. Finally, we evaluate the success of these methods to date, suggest when they are best applied, and provide our recommendations for the direction of future work.


Assuntos
Simulação por Computador , Desenho de Fármacos , Modelos Moleculares , Relação Estrutura-Atividade
13.
Curr Top Med Chem ; 5(4): 371-81, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15892680

RESUMO

Target-Related Affinity Profiling (TRAP) is a computational drug discovery technology that is based on 'affinity fingerprints', which are molecular descriptors derived from the protein binding preferences of small molecules. The underlying concepts of TRAP are reviewed. Affinity fingerprints are compared to molecular descriptors derived from chemical structures and shown to be a useful alternative for lead discovery. The TRAP screening process is described and two example applications are presented: I. the discovery of novel inhibitors of human intestinal carboxylesterase, and II. the discovery of novel inhibitors of cyclooxygenase-1 through the use of the affinity fingerprints of known cyclooxygenase-1 inhibitors. A summary of the complementary advantages of TRAP screening technology compared to traditional approaches to drug lead discovery concludes the review.


Assuntos
Desenho de Fármacos , Receptores de Droga/química , Animais , Hidrolases de Éster Carboxílico/antagonistas & inibidores , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/farmacologia , Inibidores Enzimáticos/farmacocinética , Humanos , Biologia Molecular , Prostaglandina-Endoperóxido Sintases/metabolismo , Ligação Proteica
14.
J Med Chem ; 48(8): 2906-15, 2005 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-15828829

RESUMO

Carboxylesterases (CE) are ubiquitous enzymes responsible for the metabolism of xenobiotics. Because the structural and amino acid homology among esterases of different classes, the identification of selective inhibitors of these proteins has proved problematic. Using Telik's target-related affinity profiling (TRAP) technology, we have identified a class of compounds based on benzil (1,2-diphenylethane-1,2-dione) that are potent CE inhibitors, with K(i) values in the low nanomolar range. Benzil and 30 analogues demonstrated selective inhibition of CEs, with no inhibitory activity toward human acetylcholinesterase or butyrylcholinesterase. Analysis of structurally related compounds indicated that the ethane-1,2-dione moiety was essential for enzyme inhibition and that potency was dependent on the presence of, and substitution within, the benzene ring. 3D-QSAR analyses of these benzil analogues for three different mammalian CEs demonstrated excellent correlations of observed versus predicted K(i) (r(2) > 0.91), with cross-validation coefficients (q(2)) of 0.9. Overall, these results suggest that selective inhibitors of CEs with potential for use in clinical applications can be designed.


Assuntos
Carboxilesterase/antagonistas & inibidores , Fenilglioxal/análogos & derivados , Fenilglioxal/química , Acetilcolinesterase/química , Animais , Butirilcolinesterase/química , Hidrolases de Éster Carboxílico/antagonistas & inibidores , Hidrolases de Éster Carboxílico/química , Inibidores da Colinesterase/química , Bases de Dados Factuais , Humanos , Intestinos/enzimologia , Modelos Moleculares , Fenilglioxal/síntese química , Relação Quantitativa Estrutura-Atividade , Ratos , Relação Estrutura-Atividade , Umbeliferonas/química
15.
J Med Chem ; 47(20): 4875-80, 2004 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-15369391

RESUMO

We used protein affinity fingerprints to discover structurally novel inhibitors of cyclooxygenase-1 (COX-1) by screening a selected number of compounds, thus providing an alternative to extensive screening. From the affinity fingerprints of 19 known COX-1 inhibitors, a computational model for COX-1 inhibition was constructed and used to select candidate inhibitors from our compound library to be tested in the COX-1 assay. Subsequent refinement of the model by including affinity fingerprints of inactive compounds identified three molecules that were more potent than ibuprofen, a commonly used COX-1 inhibitor. These compounds are structurally distinct from those used to build the model and were discovered by testing only 62 library compounds. The discovery of these leads demonstrates the efficiency with which affinity fingerprints can identify novel bioactive chemotypes from known drugs.


Assuntos
Técnicas de Química Combinatória/métodos , Inibidores de Ciclo-Oxigenase/química , Inibidores de Ciclo-Oxigenase/farmacologia , Isoenzimas/antagonistas & inibidores , Modelos Teóricos , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Ciclo-Oxigenase 1 , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Ibuprofeno/química , Ibuprofeno/farmacologia , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Estudos Prospectivos , Prostaglandina-Endoperóxido Sintases , Relação Quantitativa Estrutura-Atividade
16.
Mol Pharmacol ; 65(6): 1336-43, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15155827

RESUMO

The dose-limiting toxicity of the highly effective anticancer agent 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (irinotecan; CPT-11) is delayed diarrhea. This is thought to be caused by either bacteria-mediated hydrolysis of the glucuronide conjugate of the active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) or direct conversion of CPT-11 to SN-38 by carboxylesterases (CE) in the small intestine. After drug administration, a very high level of CPT-11 is present in the bile; this is deposited into the duodenum, the region of the gut with the highest levels of CE activity. Hence, it is likely that direct conversion of the drug to SN-38 is partially responsible for the diarrhea associated with this agent. In an attempt to ameliorate this toxicity, we have applied Target-Related Affinity Profiling to identify novel CE inhibitors that are selective inhibitors of the human intestinal enzyme (hiCE). Seven inhibitors, all sulfonamide derivatives, demonstrated greater than 200-fold selectivity for hiCE compared with the human liver CE hCE1, and none was an inhibitor of human acetylcholinesterase or butyrylcholinesterase. Quantitative structure-activity relationship (QSAR) analysis demonstrated excellent correlations with the predicted versus experimental Ki values (r2 = 0.944) for hiCE. Additionally, design and synthesis of a tetrafluorine-substituted sulfonamide analog, which QSAR indicated would demonstrate improved inhibition of hiCE, validated the computer predictive analyses. These and other phenyl-substituted sulfonamides compounds are regarded as lead compounds for the development of effective, selective CE inhibitors for clinical applications.


Assuntos
Camptotecina/análogos & derivados , Camptotecina/efeitos adversos , Hidrolases de Éster Carboxílico/antagonistas & inibidores , Diarreia/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Sulfonamidas/uso terapêutico , Animais , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/metabolismo , Camptotecina/metabolismo , Diarreia/induzido quimicamente , Inibidores Enzimáticos/química , Humanos , Intestinos/enzimologia , Irinotecano , Modelos Moleculares , Relação Quantitativa Estrutura-Atividade , Coelhos , Sulfonamidas/síntese química , Sulfonamidas/química
17.
J Chem Inf Comput Sci ; 42(5): 1230-40, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12377013

RESUMO

The shape of and the chemical features of a ligand are both critical for biological activity. This paper presents a strategy that uses these descriptors to build a computational model for virtual screening of bioactive compounds. Molecules are represented in a binary shape-feature descriptor space as bit-strings, and their relative activities are used to identify the subset of the bit-string that is most relevant to bioactivity. This subset is used to score virtual libraries. We describe the computational details of the method and present an example validation experiment on thrombin inhibitors.


Assuntos
Avaliação Pré-Clínica de Medicamentos/estatística & dados numéricos , Simulação por Computador , Ligantes , Modelos Químicos , Conformação Molecular , Estrutura Molecular , Interface Usuário-Computador
18.
Drug Discov Today ; 7(15): 807-14, 2002 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-12546968

RESUMO

The large number of small organic compounds now available for drug-lead screening has led to numerous methods for classifying molecular similarity and diversity, the aim being to restore a balance between the quantity and drug-like quality of compounds in small-molecule libraries. Whereas structural and physicochemical attributes continue to be emphasized in compound selection for drug-lead screening, chemoproteomics--the use of biological information to guide chemistry--offers a highly efficient alternative to small-molecule characterization that can accelerate drug discovery in the post-genomic era.


Assuntos
Indústria Farmacêutica/tendências , Preparações Farmacêuticas/química , Proteoma , Bases de Dados Factuais , Desenho de Fármacos
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