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1.
Nat Chem Biol ; 20(9): 1164-1175, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38773330

RESUMO

The C-terminal to LisH (CTLH) complex is a ubiquitin ligase complex that recognizes substrates with Pro/N-degrons via its substrate receptor Glucose-Induced Degradation 4 (GID4), but its function and substrates in humans remain unclear. Here, we report PFI-7, a potent, selective and cell-active chemical probe that antagonizes Pro/N-degron binding to human GID4. Use of PFI-7 in proximity-dependent biotinylation and quantitative proteomics enabled the identification of GID4 interactors and GID4-regulated proteins. GID4 interactors are enriched for nucleolar proteins, including the Pro/N-degron-containing RNA helicases DDX21 and DDX50. We also identified a distinct subset of proteins whose cellular levels are regulated by GID4 including HMGCS1, a Pro/N-degron-containing metabolic enzyme. These data reveal human GID4 Pro/N-degron targets regulated through a combination of degradative and nondegradative functions. Going forward, PFI-7 will be a valuable research tool for investigating CTLH complex biology and facilitating development of targeted protein degradation strategies that highjack CTLH E3 ligase activity.


Assuntos
Ligação Proteica , Humanos , Proteólise , Células HEK293 , Sondas Moleculares/química , Sondas Moleculares/metabolismo , RNA Helicases DEAD-box/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Degrons , Receptores de Interleucina-17
2.
Bioorg Med Chem Lett ; 98: 129546, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-37944866

RESUMO

Epigenetic proteins containing YEATS domains (YD) are an emerging target class in drug discovery. Described herein are the discovery and characterization efforts associated with PFI-6, a new chemical probe for the YD of MLLT1 (ENL/YEATS1) and MLLT3 (AF9/YEATS3). For hit identification, fragment-like mimetics of endogenous YD ligands (crotonylated histone-containing proteins), were synthesized via parallel medicinal chemistry (PMC) and screened for MLLT1 binding. Subsequent SAR studies led to iterative MLLT1/3 binding and selectivity improvements, culminating in the discovery of PFI-6. PFI-6 demonstrates good affinity and selectivity for MLLT1/3 vs. other human YD proteins (YEATS2/4) and engages MLLT3 in cells. Small-molecule X-ray co-crystal structures of two molecules, including PFI-6, bound to the YD of MLLT1/3 are also described. PFI-6 may be a useful tool molecule to better understand the biological effects associated with modulation of MLLT1/3.


Assuntos
Histonas , Proteínas Nucleares , Humanos , Proteínas Nucleares/metabolismo , Histonas/metabolismo , Domínios Proteicos , Descoberta de Drogas , Proteínas de Neoplasias/metabolismo , Fatores de Transcrição/metabolismo
3.
Proc Natl Acad Sci U S A ; 111(35): 12853-8, 2014 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-25136132

RESUMO

SET domain containing (lysine methyltransferase) 7 (SETD7) is implicated in multiple signaling and disease related pathways with a broad diversity of reported substrates. Here, we report the discovery of (R)-PFI-2-a first-in-class, potent (Ki (app) = 0.33 nM), selective, and cell-active inhibitor of the methyltransferase activity of human SETD7-and its 500-fold less active enantiomer, (S)-PFI-2. (R)-PFI-2 exhibits an unusual cofactor-dependent and substrate-competitive inhibitory mechanism by occupying the substrate peptide binding groove of SETD7, including the catalytic lysine-binding channel, and by making direct contact with the donor methyl group of the cofactor, S-adenosylmethionine. Chemoproteomics experiments using a biotinylated derivative of (R)-PFI-2 demonstrated dose-dependent competition for binding to endogenous SETD7 in MCF7 cells pretreated with (R)-PFI-2. In murine embryonic fibroblasts, (R)-PFI-2 treatment phenocopied the effects of Setd7 deficiency on Hippo pathway signaling, via modulation of the transcriptional coactivator Yes-associated protein (YAP) and regulation of YAP target genes. In confluent MCF7 cells, (R)-PFI-2 rapidly altered YAP localization, suggesting continuous and dynamic regulation of YAP by the methyltransferase activity of SETD7. These data establish (R)-PFI-2 and related compounds as a valuable tool-kit for the study of the diverse roles of SETD7 in cells and further validate protein methyltransferases as a druggable target class.


Assuntos
Inibidores Enzimáticos/farmacologia , Epigênese Genética/efeitos dos fármacos , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Histona-Lisina N-Metiltransferase/metabolismo , Pirrolidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Tetra-Hidroisoquinolinas/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Fibroblastos/efeitos dos fármacos , Via de Sinalização Hippo , Histona-Lisina N-Metiltransferase/genética , Humanos , Células MCF-7 , Metiltransferases/antagonistas & inibidores , Metiltransferases/metabolismo , Mutação , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinases/genética , Estrutura Terciária de Proteína , Pirrolidinas/química , Relação Estrutura-Atividade , Sulfonamidas/química , Tetra-Hidroisoquinolinas/química , Fatores de Transcrição , Proteínas de Sinalização YAP
4.
Drug Discov Today Technol ; 12: e29-34, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25027371

RESUMO

While the installation and removal of epigenetic post-translational modifications or 'marks' on both DNA and histone proteins are the tangible outcome of enzymatically catalyzed processes, the role of the epigenetic reader proteins looks, at first, less obvious. As they do not catalyze a chemical transformation or process as such, their role is not enzymatic. However, this does not preclude them from being potential targets for drug discovery as their function is clearly correlated to transcriptional activity and as a class of proteins, they appear to have binding sites of sufficient definition and size to be inhibited by small molecules. This suggests that this third class of epigenetic proteins that are involved in the interpretation of post-translational marks (as opposed to the creation or deletion of marks) may represent attractive targets for drug discovery efforts. This review mainly summarizes selected publications, patent literature and company disclosures on these non-enzymatic epigenetic reader proteins from 2009 to the present.


Assuntos
Metilases de Modificação do DNA/metabolismo , Descoberta de Drogas , Epigênese Genética/efeitos dos fármacos , Histona Acetiltransferases/metabolismo , Histona Desacetilases/metabolismo , Animais , Sítios de Ligação , Metilação de DNA/efeitos dos fármacos , Epigênese Genética/genética , Histonas/genética , Histonas/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Processamento de Proteína Pós-Traducional , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia
5.
Nat Commun ; 15(1): 5640, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38965235

RESUMO

The Structural Genomics Consortium is an international open science research organization with a focus on accelerating early-stage drug discovery, namely hit discovery and optimization. We, as many others, believe that artificial intelligence (AI) is poised to be a main accelerator in the field. The question is then how to best benefit from recent advances in AI and how to generate, format and disseminate data to enable future breakthroughs in AI-guided drug discovery. We present here the recommendations of a working group composed of experts from both the public and private sectors. Robust data management requires precise ontologies and standardized vocabulary while a centralized database architecture across laboratories facilitates data integration into high-value datasets. Lab automation and opening electronic lab notebooks to data mining push the boundaries of data sharing and data modeling. Important considerations for building robust machine-learning models include transparent and reproducible data processing, choosing the most relevant data representation, defining the right training and test sets, and estimating prediction uncertainty. Beyond data-sharing, cloud-based computing can be harnessed to build and disseminate machine-learning models. Important vectors of acceleration for hit and chemical probe discovery will be (1) the real-time integration of experimental data generation and modeling workflows within design-make-test-analyze (DMTA) cycles openly, and at scale and (2) the adoption of a mindset where data scientists and experimentalists work as a unified team, and where data science is incorporated into the experimental design.


Assuntos
Ciência de Dados , Descoberta de Drogas , Aprendizado de Máquina , Descoberta de Drogas/métodos , Ciência de Dados/métodos , Humanos , Inteligência Artificial , Disseminação de Informação/métodos , Mineração de Dados/métodos , Computação em Nuvem , Bases de Dados Factuais
6.
RSC Med Chem ; 15(3): 1066-1071, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38516600

RESUMO

We have developed a novel chemical handle (PFI-E3H1) and a chemical probe (PFI-7) as ligands for the Gid4 subunit of the human E3 ligase CTLH degradation complex. Through an efficient initial hit-ID campaign, structure-based drug design (SBDD) and leveraging the sizeable Pfizer compound library, we identified a 500 nM ligand for this E3 ligase through file screening alone. Further exploration identified a vector that is tolerant to addition of a linker for future chimeric molecule design. The chemotype was subsequently optimized to sub-100 nM Gid4 binding affinity for a chemical probe. These novel tools, alongside the suitable negative control also identified, should enable the interrogation of this complex human E3 ligase macromolecular assembly.

7.
J Med Chem ; 67(16): 13550-13571, 2024 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-38687966

RESUMO

Despite the record-breaking discovery, development and approval of vaccines and antiviral therapeutics such as Paxlovid, coronavirus disease 2019 (COVID-19) remained the fourth leading cause of death in the world and third highest in the United States in 2022. Here, we report the discovery and characterization of PF-07817883, a second-generation, orally bioavailable, SARS-CoV-2 main protease inhibitor with improved metabolic stability versus nirmatrelvir, the antiviral component of the ritonavir-boosted therapy Paxlovid. We demonstrate the in vitro pan-human coronavirus antiviral activity and off-target selectivity profile of PF-07817883. PF-07817883 also demonstrated oral efficacy in a mouse-adapted SARS-CoV-2 model at plasma concentrations equivalent to nirmatrelvir. The preclinical in vivo pharmacokinetics and metabolism studies in human matrices are suggestive of improved oral pharmacokinetics for PF-07817883 in humans, relative to nirmatrelvir. In vitro inhibition/induction studies against major human drug metabolizing enzymes/transporters suggest a low potential for perpetrator drug-drug interactions upon single-agent use of PF-07817883.


Assuntos
Antivirais , Tratamento Farmacológico da COVID-19 , Inibidores de Proteases , SARS-CoV-2 , Humanos , Animais , Camundongos , SARS-CoV-2/efeitos dos fármacos , Antivirais/farmacologia , Antivirais/farmacocinética , Antivirais/uso terapêutico , Antivirais/química , Administração Oral , Inibidores de Proteases/farmacologia , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/uso terapêutico , Inibidores de Proteases/química , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/metabolismo , Ratos , COVID-19/virologia
8.
J Med Chem ; 66(1): 460-472, 2023 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-36562986

RESUMO

A series of small-molecule YEATS4 binders have been discovered as part of an ongoing research effort to generate high-quality probe molecules for emerging and/or challenging epigenetic targets. Analogues such as 4d and 4e demonstrate excellent potency and selectivity for YEATS4 binding versus YEATS1,2,3 and exhibit good physical properties and in vitro safety profiles. A new X-ray crystal structure confirms direct binding of this chemical series to YEATS4 at the lysine acetylation recognition site of the YEATS domain. Multiple analogues engage YEATS4 with nanomolar potency in a whole-cell nanoluciferase bioluminescent resonance energy transfer assay. Rodent pharmacokinetic studies demonstrate the competency of several analogues as in vivo-capable binders.


Assuntos
Regulação da Expressão Gênica , Processamento de Proteína Pós-Traducional , Domínios Proteicos , Acetilação , Epigênese Genética
9.
RSC Med Chem ; 14(6): 1002-1011, 2023 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-37360399

RESUMO

Target 2035, an international federation of biomedical scientists from the public and private sectors, is leveraging 'open' principles to develop a pharmacological tool for every human protein. These tools are important reagents for scientists studying human health and disease and will facilitate the development of new medicines. It is therefore not surprising that pharmaceutical companies are joining Target 2035, contributing both knowledge and reagents to study novel proteins. Here, we present a brief progress update on Target 2035 and highlight some of industry's contributions.

12.
RSC Med Chem ; 13(1): 13-21, 2022 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-35211674

RESUMO

Twenty years after the publication of the first draft of the human genome, our knowledge of the human proteome is still fragmented. The challenge of translating the wealth of new knowledge from genomics into new medicines is that proteins, and not genes, are the primary executers of biological function. Therefore, much of how biology works in health and disease must be understood through the lens of protein function. Accordingly, a subset of human proteins has been at the heart of research interests of scientists over the centuries, and we have accumulated varying degrees of knowledge about approximately 65% of the human proteome. Nevertheless, a large proportion of proteins in the human proteome (∼35%) remains uncharacterized, and less than 5% of the human proteome has been successfully targeted for drug discovery. This highlights the profound disconnect between our abilities to obtain genetic information and subsequent development of effective medicines. Target 2035 is an international federation of biomedical scientists from the public and private sectors, which aims to address this gap by developing and applying new technologies to create by year 2035 chemogenomic libraries, chemical probes, and/or biological probes for the entire human proteome.

13.
Bioorg Med Chem Lett ; 21(14): 4284-7, 2011 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-21669533

RESUMO

A series of benzimidazole CB(2) receptor agonists were prepared and their properties investigated. Optimisation of the three benzimidazole substituents led to the identification of compound 23, a potent CB(2) full agonist (EC(50) 2.7nM) with excellent selectivity over the CB(1) receptor (>3000-fold). Compound 23 demonstrated good CNS penetration in rat. Further optimisation led to the identification of compound 34 with improved selectivity over hERG and excellent CNS penetration in rat.


Assuntos
Analgésicos/química , Benzimidazóis/química , Sistema Nervoso Central/metabolismo , Receptor CB2 de Canabinoide/agonistas , Analgésicos/síntese química , Analgésicos/farmacocinética , Animais , Benzimidazóis/síntese química , Benzimidazóis/farmacocinética , Microssomos Hepáticos/metabolismo , Ratos , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-Atividade
14.
Bioorg Med Chem Lett ; 21(11): 3404-6, 2011 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-21515054

RESUMO

Heteroarylalanine derivatives 4 were designed as potential inhibitors of neutral endopeptidase (NEP EC 3.4.24.11). Selectivity over other zinc metalloproteinases was explored through occupation of the S2' subsite within NEP. Structural optimisation led to the identification of 5-phenyl oxazole 4f, a potent and selective NEP inhibitor. A crystal structure of the inhibitor bound complex is reported.


Assuntos
Ácidos/síntese química , Alanina/síntese química , Neprilisina/antagonistas & inibidores , Oxazóis/química , Oxazóis/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Ácidos/química , Ácidos/farmacologia , Alanina/química , Alanina/farmacologia , Cristalografia por Raios X , Ativação Enzimática/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteases/química
15.
ACS Chem Biol ; 16(4): 571-578, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33749253

RESUMO

Dysfunction of YEATS-domain-containing MLLT1, an acetyl/acyl-lysine dependent epigenetic reader domain, has been implicated in the development of aggressive cancers. Mutations in the YEATS domain have been recently reported as a cause of MLLT1 aberrant reader function. However, the structural basis for the reported alterations in affinity for acetylated/acylated histone has remained elusive. Here, we report the crystal structures of both insertion and substitution mutants present in cancer, revealing significant conformational changes of the YEATS-domain loop 8. Structural comparison demonstrates that not only did such alteration alter the binding interface for acetylated/acylated histones, but the sequence alterations in the loop in T1 mutant may enable dimeric assembly consistent with inducing self-association behavior. Nevertheless, we show that also the MLLT1 mutants can be targeted by developed acetyllysine mimetic inhibitors with affinities similarly to wild-type. Our report provides a structural basis for the altered behaviors and a potential strategy for targeting oncogenic MLLT1 mutants.


Assuntos
Mutação , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Humanos , Proteínas de Neoplasias/química , Proteínas de Neoplasias/genética , Proteínas Nucleares/química , Proteínas Nucleares/genética , Conformação Proteica , Fatores de Transcrição/química , Fatores de Transcrição/genética
16.
RSC Med Chem ; 12(12): 2045-2052, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-35024613

RESUMO

Oxetanes have received increasing interest in medicinal chemistry as attractive polar and low molecular weight motifs. The application of oxetanes as replacements for methylene, methyl, gem-dimethyl and carbonyl groups has been demonstrated to often improve chemical properties of target molecules for drug discovery purposes. The investigation of the properties of 3,3-diaryloxetanes, particularly of interest as a benzophenone replacement, remains largely unexplored. With recent synthetic advances in accessing this motif we studied the effects of 3,3-diaryloxetanes on the physicochemical properties of 'drug-like' molecules. Here, we describe our efforts in the design and synthesis of a range of drug-like compounds for matched molecular pair analysis to investigate the viability of the 3,3-diaryloxetane motif as a replacement group in drug discovery. We conclude that the properties of the diaryloxetanes and ketones are similar, and generally superior to related alkyl linkers, and that diaryloxetanes provide a potentially useful new design element.

17.
Science ; 374(6575): 1586-1593, 2021 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-34726479

RESUMO

The worldwide outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to countering the ongoing threat presented by COVID-19. Here, we report the discovery and characterization of PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus antiviral activity and excellent off-target selectivity and in vivo safety profiles. PF-07321332 has demonstrated oral activity in a mouse-adapted SARS-CoV-2 model and has achieved oral plasma concentrations exceeding the in vitro antiviral cell potency in a phase 1 clinical trial in healthy human participants.


Assuntos
Tratamento Farmacológico da COVID-19 , Lactamas/farmacologia , Lactamas/uso terapêutico , Leucina/farmacologia , Leucina/uso terapêutico , Nitrilas/farmacologia , Nitrilas/uso terapêutico , Prolina/farmacologia , Prolina/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , Inibidores de Protease Viral/farmacologia , Inibidores de Protease Viral/uso terapêutico , Administração Oral , Animais , COVID-19/virologia , Ensaios Clínicos Fase I como Assunto , Coronavirus/efeitos dos fármacos , Modelos Animais de Doenças , Quimioterapia Combinada , Humanos , Lactamas/administração & dosagem , Lactamas/farmacocinética , Leucina/administração & dosagem , Leucina/farmacocinética , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Nitrilas/administração & dosagem , Nitrilas/farmacocinética , Prolina/administração & dosagem , Prolina/farmacocinética , Ensaios Clínicos Controlados Aleatórios como Assunto , Ritonavir/administração & dosagem , Ritonavir/uso terapêutico , SARS-CoV-2/fisiologia , Inibidores de Protease Viral/administração & dosagem , Inibidores de Protease Viral/farmacocinética , Replicação Viral/efeitos dos fármacos
18.
Bioorg Med Chem Lett ; 20(1): 92-6, 2010 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-19954973

RESUMO

A suitable inhibitor of activated thrombin activatable fibrinolysis inhibitor (TAFIa) has the potential to be a novel treatment for thrombosis. The TAFIa inhibitor UK-396082 (1) was used as a starting point to seek more potent analogues. With knowledge of encouraging human pharmacokinetics and toleration for the clinical candidate (1), the programme continued to seek structure-activity relationships (SAR) that could positively impact on both potency and half-life, and therefore the projected dose of any future nominated clinical agent. A series of oxygenated analogues based on compound 1 were prepared to evaluate changes in pharmacology, selectivity and pharmacokinetics.


Assuntos
Aminoácidos/química , Carboxipeptidase B2/antagonistas & inibidores , Fibrinolíticos/química , Imidazóis/química , Oxigênio/química , Inibidores de Proteases/química , Administração Oral , Aminoácidos/síntese química , Aminoácidos/farmacocinética , Animais , Carboxipeptidase B2/metabolismo , Fibrinolíticos/síntese química , Fibrinolíticos/farmacocinética , Meia-Vida , Humanos , Imidazóis/síntese química , Imidazóis/farmacocinética , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Ratos , Relação Estrutura-Atividade
19.
J Med Chem ; 63(22): 13561-13577, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-32787094

RESUMO

Tyrosine kinase 2 (TYK2) is a member of the JAK kinase family that regulates signal transduction downstream of receptors for the IL-23/IL-12 pathways and type I interferon family, where it pairs with JAK2 or JAK1, respectively. On the basis of human genetic and emerging clinical data, a selective TYK2 inhibitor provides an opportunity to treat autoimmune diseases delivering a potentially differentiated clinical profile compared to currently approved JAK inhibitors. The discovery of an ATP-competitive pyrazolopyrazinyl series of TYK2 inhibitors was accomplished through computational and structurally enabled design starting from a known kinase hinge binding motif. With understanding of PK/PD relationships, a target profile balancing TYK2 potency and selectivity over off-target JAK2 was established. Lead optimization involved modulating potency, selectivity, and ADME properties which led to the identification of the clinical candidate PF-06826647 (22).


Assuntos
Doenças Autoimunes/enzimologia , Descoberta de Drogas/métodos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , TYK2 Quinase/antagonistas & inibidores , Animais , Doenças Autoimunes/tratamento farmacológico , Humanos , Camundongos , Camundongos Transgênicos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Inibidores de Proteínas Quinases/uso terapêutico , Estrutura Secundária de Proteína , TYK2 Quinase/química , TYK2 Quinase/metabolismo
20.
Bioorg Med Chem Lett ; 19(15): 4406-9, 2009 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-19500981

RESUMO

A series of libraries were designed using the 1-(cyclopropylmethyl)-2-alkyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-5-ium templates 2a-b, and Sulfonamide derivatives 11a-n proved to be potent agonists of the CB(2) receptor. Analysis of the Lipophilic Efficiency (LipE) of potent compounds provided new insight for the design of potent, metabolically stable CB2 agonists.


Assuntos
Receptor CB2 de Canabinoide/química , Animais , Sítios de Ligação , Química Farmacêutica/métodos , Técnicas de Química Combinatória , Desenho de Fármacos , Concentração Inibidora 50 , Ligantes , Microssomos Hepáticos/efeitos dos fármacos , Modelos Químicos , Estrutura Molecular , Nitrogênio/química , Ratos , Relação Estrutura-Atividade , Sulfonamidas/química
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