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1.
J Med Chem ; 65(21): 14261-14275, 2022 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-36282210

RESUMO

Hydrogen-bond donors are seen to cause more problems for drug designers than hydrogen-bond acceptors. Most of the polarity in drug-like compounds comes from hydrogen-bond acceptors since they typically exceed the hydrogen-bond donors in number and are more heavily solvated on an individual basis. The implications of this polarity imbalance for optimization of permeability and aqueous solubility are discussed. A factor that should be considered in optimization of ligand recognition by targets is that the presence of a hydrogen-bond donor generally implies that a hydrogen-bond acceptor is also present (but not vice versa). Frustrated solvation and secondary electrostatic interactions result from aligned hydrogen-bond donors and acceptors, and the design opportunities presented by these phenomena are discussed. Hydrogen-bond donors based on oxygen, nitrogen and carbon are compared as target recognition elements, and halogen- and chalcogen-bond donors are discussed as hydrogen-bond donor equivalents.


Assuntos
Halogênios , Hidrogênio , Ligação de Hidrogênio , Eletricidade Estática , Halogênios/química , Desenho de Fármacos
2.
J Chem Inf Model ; 62(17): 4083-4094, 2022 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-36044342

RESUMO

We have used molecular dynamics (MD) simulations with hybrid quantum mechanics/molecular mechanics (QM/MM) potentials to investigate the reaction mechanism for covalent inhibition of cathepsin K and assess the reversibility of inhibition. The computed free energy profiles suggest that a nucleophilic attack by the catalytic cysteine on the inhibitor warhead and proton transfer from the catalytic histidine occur in a concerted manner. The results indicate that the reaction is more strongly exergonic for the alkyne-based inhibitors, which bind irreversibly to cathepsin K, than for the nitrile-based inhibitor odanacatib, which binds reversibly. Gas-phase energies were also calculated for the addition of methanethiol to structural prototypes for a number of warheads of interest in cysteine protease inhibitor design in order to assess electrophilicity. The approaches presented in this study are particularly applicable to assessment of novel warheads, and computed transition state geometries can be incorporated into molecular models for covalent docking.


Assuntos
Inibidores de Cisteína Proteinase , Simulação de Dinâmica Molecular , Catálise , Catepsina K/metabolismo , Inibidores de Cisteína Proteinase/química , Inibidores de Proteases , Teoria Quântica
3.
Bioorg Med Chem ; 28(22): 115743, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-33038787

RESUMO

Leishmania mexicana is an obligate intracellular protozoan parasite that causes the cutaneous form of leishmaniasis affecting South America and Mexico. The cysteine protease LmCPB is essential for the virulence of the parasite and therefore, it is an appealing target for antiparasitic therapy. A library of nitrile-based cysteine protease inhibitors was screened against LmCPB to develop a treatment of cutaneous leishmaniasis. Several compounds are sufficiently high-affinity LmCPB inhibitors to serve both as starting points for drug discovery projects and as probes for target validation. A 1.4 Å X ray crystal structure, the first to be reported for LmCPB, was determined for the complex of this enzyme covalently bound to an azadipeptide nitrile ligand. Mapping the structure-activity relationships for LmCPB inhibition revealed superadditive effects for two pairs of structural transformations. Therefore, this work advances our understanding of azadipeptidyl and dipeptidyl nitrile structure-activity relationships for LmCPB structure-based inhibitor design. We also tested the same series of inhibitors on related cysteine proteases cathepsin L and Trypanosoma cruzi cruzain. The modulation of these mammalian and protozoan proteases represents a new framework for targeting papain-like cysteine proteases.


Assuntos
Compostos Aza/farmacologia , Catepsina B/antagonistas & inibidores , Inibidores de Cisteína Proteinase/farmacologia , Leishmania mexicana/efeitos dos fármacos , Tripanossomicidas/farmacologia , Compostos Aza/síntese química , Compostos Aza/química , Catepsina B/metabolismo , Cristalografia por Raios X , Cisteína Endopeptidases/metabolismo , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/química , Dipeptídeos/síntese química , Dipeptídeos/química , Dipeptídeos/farmacologia , Relação Dose-Resposta a Droga , Leishmania mexicana/enzimologia , Simulação de Dinâmica Molecular , Estrutura Molecular , Nitrilas/síntese química , Nitrilas/química , Nitrilas/farmacologia , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/metabolismo , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química
4.
Bioorg Med Chem ; 27(22): 115083, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31561938

RESUMO

The structure-activity relationship for nitrile-based cruzain inhibitors incorporating a P2 amide replacement based on trifluoroethylamine was explored by deconstruction of a published series of inhibitors. It was demonstrated that the P3 biphenyl substituent present in the published inhibitor structures could be truncated to phenyl with only a small loss of affinity. The effects of inverting the configuration of the P2 amide replacement and linking a benzyl substituent at P1 were observed to be strongly nonadditive. We show that plotting affinity against molecular size provides a means to visualize both the molecular size efficiency of structural transformations and the nonadditivity in the structure-activity relationship. We also show how the relationship between affinity and lipophilicity, measured by high-performance liquid chromatography with an immobilized artificial membrane stationary phase, may be used to normalize affinity with respect to lipophilicity.


Assuntos
Amidas/química , Cisteína Endopeptidases/síntese química , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/síntese química , Estrutura Molecular , Relação Estrutura-Atividade
5.
J Cheminform ; 11(1): 8, 2019 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-30706294

RESUMO

Ligand efficiency is a widely used design parameter in drug discovery. It is calculated by scaling affinity by molecular size and has a nontrivial dependency on the concentration unit used to express affinity that stems from the inability of the logarithm function to take dimensioned arguments. Consequently, perception of efficiency varies with the choice of concentration unit and it is argued that the ligand efficiency metric is not physically meaningful nor should it be considered to be a metric. The dependence of ligand efficiency on the concentration unit can be eliminated by defining efficiency in terms of sensitivity of affinity to molecular size and this is illustrated with reference to fragment-to-lead optimizations. Group efficiency and fit quality are also examined in detail from a physicochemical perspective. The importance of examining relationships between affinity and molecular size directly is stressed throughout this study and an alternative to ligand efficiency for normalization of affinity with respect to molecular size is presented.

6.
J Chem Inf Model ; 57(11): 2640-2645, 2017 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-29048168

RESUMO

A recent editorial (Aldrich et al. The Ecstasy and Agony of Assay Interference Compounds . J. Chem. Inf. MODEL: 2017 , 57 , 387 - 390 ) is examined critically. When assessing assay hits from screening, it is important to draw a distinction between false positives, that have no effect on target function, and compounds that affect target function through an undesirable mechanism of action. Observation of frequent-hitter behavior for a compound should be regarded as circumstantial evidence, rather than definitive proof, that the compound has interfered with assay readouts or acted through an undesirable mechanism of action. The applicability domain of published (Baell and Holloway J. Med. Chem. 2010 , 53 , 2719 - 2740 ) Pan Assay INterference compoundS (PAINS) filters is limited by the narrow scope of the proprietary data used to derive them. It is suggested that journal guidelines for authors should not prescribe, as those for the Journal of Medicinal Chemistry appear to do, that activity in assays reported for compounds that match PAINS filters be treated any differently from that for compounds that do not match PAINS filters. It is argued that use of models based on proprietary data in the evaluation of manuscripts would contradict the editorial policy of any journal that deemed the use of proprietary data to be unacceptable in modeling studies.


Assuntos
Descoberta de Drogas/métodos , Ensaios de Triagem em Larga Escala/métodos , Interpretação Estatística de Dados
7.
Bioorg Med Chem Lett ; 27(22): 5031-5035, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-29054358

RESUMO

The effects on potency of cruzain inhibition of replacing a nitrile group with alternative warheads were explored. The oxime was almost an order of magnitude more potent than the corresponding nitrile and has the potential to provide access to the prime side of the catalytic site. Dipeptide aldehydes and azadipeptide nitriles were found to be two orders of magnitude more potent cruzain inhibitors than the corresponding dipeptide nitriles although potency differences were modulated by substitution at P1 and P3. Replacement of the α methylene of a dipeptide aldehyde with cyclopropane led to a loss of potency of almost three orders of magnitude. The vinyl esters and amides that were characterized as reversible inhibitors were less potent than the corresponding nitrile by between one and two orders of magnitude.


Assuntos
Cisteína Endopeptidases/metabolismo , Inibidores de Cisteína Proteinase/química , Domínio Catalítico , Catepsina L/química , Catepsina L/metabolismo , Cisteína Endopeptidases/química , Inibidores de Cisteína Proteinase/metabolismo , Dipeptídeos/química , Desenho de Fármacos , Cinética , Nitrilas/química , Relação Estrutura-Atividade
8.
PLoS Negl Trop Dis ; 11(2): e0005343, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28222138

RESUMO

The cysteine protease cruzipain is considered to be a validated target for therapeutic intervention in the treatment of Chagas disease. Anti-trypanosomal activity against the CL Brener strain of T. cruzi was observed in the 0.1 µM to 1 µM range for three nitrile-based cysteine protease inhibitors based on two scaffolds known to be associated with cathepsin K inhibition. The two compounds showing the greatest potency against the trypanosome were characterized by EC50 values (0.12 µM and 0.25 µM) that were an order of magnitude lower than the corresponding Ki values measured against cruzain, a recombinant form of cruzipain, in an enzyme inhibition assay. This implies that the anti-trypanosomal activity of these two compounds may not be explained only by the inhibition of the cruzain enzyme, thereby triggering a putative polypharmacological profile towards cysteine proteases.


Assuntos
Inibidores de Cisteína Proteinase/farmacologia , Nitrilas/farmacologia , Tripanossomicidas/farmacologia , Cisteína Endopeptidases , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/química , Modelos Moleculares , Estrutura Molecular , Nitrilas/síntese química , Nitrilas/química , Testes de Sensibilidade Parasitária , Proteínas de Protozoários/antagonistas & inibidores , Tripanossomicidas/síntese química , Tripanossomicidas/química , Trypanosoma cruzi/efeitos dos fármacos
9.
J Comput Aided Mol Des ; 31(2): 163-181, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28054187

RESUMO

This Perspective explores how consideration of hydrogen bonding can be used to both predict and better understand partition coefficients. It is shown how polarity of both compounds and substructures can be estimated from measured alkane/water partition coefficients. When polarity is defined in this manner, hydrogen bond donors are typically less polar than hydrogen bond acceptors. Analysis of alkane/water partition coefficients in conjunction with molecular electrostatic potential calculations suggests that aromatic chloro substituents may be less lipophilic than is generally believed and that some of the effect of chloro-substitution stems from making the aromatic π-cloud less available to hydrogen bond donors. Relationships between polarity and calculated hydrogen bond basicity are derived for aromatic nitrogen and carbonyl oxygen. Aligned hydrogen bond acceptors appear to present special challenges for prediction of alkane/water partition coefficients and this may reflect 'frustration' of solvation resulting from overlapping hydration spheres. It is also shown how calculated hydrogen bond basicity can be used to model the effect of aromatic aza-substitution on octanol/water partition coefficients.


Assuntos
Alcanos/química , Modelos Moleculares , Água/química , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Solubilidade , Eletricidade Estática
10.
J Med Chem ; 59(9): 4278-88, 2016 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-26872049

RESUMO

Hydrogen bonding is discussed in the context of medicinal chemistry design. Minimized molecular electrostatic potential (Vmin) is shown to be an effective predictor of hydrogen bond basicity (pKBHX), and predictive models are presented for a number of hydrogen bond acceptor types relevant to medicinal chemistry. The problems posed by the presence of nonequivalent hydrogen bond acceptor sites in molecular structures are addressed by using nonlinear regression to fit measured pKBHX to calculated Vmin. Predictions are made for hydrogen bond basicity of fluorine in situations where relevant experimental measurements are not available. It is shown how predicted pKBHX can be used to provide insight into the nature of bioisosterism and to profile heterocycles. Examples of pKBHX prediction for molecular structures with multiple, nonequivalent hydrogen bond acceptors are presented.


Assuntos
Química Farmacêutica , Desenho de Fármacos , Flúor/química , Ligação de Hidrogênio , Concentração de Íons de Hidrogênio
11.
PLoS Negl Trop Dis ; 9(7): e0003916, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26173110

RESUMO

A series of compounds based on the dipeptidyl nitrile scaffold were synthesized and assayed for their inhibitory activity against the T. cruzi cysteine protease cruzain. Structure activity relationships (SARs) were established using three, eleven and twelve variations respectively at the P1, P2 and P3 positions. A Ki value of 16 nM was observed for the most potent of these inhibitors which reflects a degree of non-additivity in the SAR. An X-ray crystal structure was determined for the ligand-protein complex for the structural prototype for the series. Twenty three inhibitors were also evaluated for their anti-trypanosomal effects and an EC50 value of 28 µM was observed for the most potent of these. Although there remains scope for further optimization, the knowledge gained from this study is also transferable to the design of cruzain inhibitors based on warheads other than nitrile as well as alternative scaffolds.


Assuntos
Doença de Chagas/parasitologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Tripanossomicidas/síntese química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Sítios de Ligação , Doença de Chagas/tratamento farmacológico , Cristalografia por Raios X , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , Desenho de Fármacos , Inibidores Enzimáticos/química , Humanos , Cinética , Nitrilas/química , Nitrilas/farmacologia , Proteínas de Protozoários/química , Proteínas de Protozoários/metabolismo , Relação Estrutura-Atividade , Tripanossomicidas/química , Trypanosoma cruzi/enzimologia
12.
J Comput Aided Mol Des ; 28(7): 699-710, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24899110

RESUMO

Ligand efficiency metrics are used in drug discovery to normalize biological activity or affinity with respect to physicochemical properties such as lipophilicity and molecular size. This Perspective provides an overview of ligand efficiency metrics and summarizes thermodynamics of protein-ligand binding. Different classes of ligand efficiency metric are critically examined and the study concludes with suggestions for alternative ways to account for physicochemical properties when prioritizing and optimizing leads.


Assuntos
Ligantes , Proteínas/química , Termodinâmica , Descoberta de Drogas , Humanos , Ligação Proteica
13.
Acta Crystallogr D Biol Crystallogr ; 70(Pt 2): 565-71, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24531490

RESUMO

The X-ray crystal structure of the complex of protein tyrosine phosphatase 1B with nitrate anion has been determined and modelled quantum-mechanically. Two protomers were present in the structure, one with the mechanistically important WPD loop closed and the other with this loop open. Nitrate was observed bound to each protomer, making close contacts with the S atom of the catalytic cysteine and a tyrosine residue from a crystallographically related protomer.


Assuntos
Mimetismo Molecular , Nitratos/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/química , Biocatálise , Domínio Catalítico , Cristalografia por Raios X , Escherichia coli/genética , Escherichia coli/metabolismo , Humanos , Ligantes , Modelos Moleculares , Nitratos/metabolismo , Regiões Promotoras Genéticas , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Teoria Quântica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Especificidade por Substrato
14.
J Comput Aided Mol Des ; 27(8): 655-64, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24002455

RESUMO

The ability to modify chemical structures in an automated and controlled manner is useful in molecular design. This Perspective introduces the MUDO molecule editor and shows how automated molecule editing can be used to standardize structures, enumerate tautomeric and ionization states, identify matched molecular pairs. Unlike its predecessor Leatherface, MUDO can also process 3D structures and this capability can be used to link non-covalently docked ligands to proteins.


Assuntos
Desenho Assistido por Computador , Sítios de Ligação , Isomerismo , Ligantes , Conformação Molecular , Simulação de Acoplamento Molecular , Proteínas/metabolismo
15.
J Comput Aided Mol Des ; 27(5): 389-402, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23737238

RESUMO

Alkane/water partition coefficients (P(alk)) are less familiar to the molecular design community than their 1-octanol/water equivalents and access to both data and prediction tools is much more limited. A method for predicting alkane/water partition coefficient from molecular structure is introduced. The basis for the ClogP(alk) model is the strong (R² = 0.987) relationship between alkane/water partition coefficient and molecular surface area (MSA) that was observed for saturated hydrocarbons. The model treats a molecule as a perturbation of a saturated hydrocarbon molecule with the same MSA and uses increments defined for functional groups to quantify the extent to which logP(alk) is perturbed by the introduction each functional group. Interactions between functional groups, such as intramolecular hydrogen bonds are also parameterized within a perturbation framework. The functional groups and interactions between them are specified substructurally in a transparent and reproducible manner using SMARTS notation. The ClogP(alk) model was parameterized using data measured for structurally prototypical compounds that dominate the literature on alkane/water partition coefficients and then validated using an external test set of 100 alkane/water logP measurements, the majority of which were for drugs.


Assuntos
Alcanos/química , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade , Água/química , 1-Octanol/química , Descoberta de Drogas , Ligação de Hidrogênio , Modelos Químicos , Solubilidade
16.
J Comput Aided Mol Des ; 27(1): 1-13, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23306465

RESUMO

Drug-likeness is a frequently invoked, although not always precisely defined, concept in drug discovery. Opinions on drug-likeness are to a large extent shaped by the relationships that are observed between surrogate measures of drug-likeness (e.g. aqueous solubility; permeability; pharmacological promiscuity) and fundamental physicochemical properties (e.g. lipophilicity; molecular size). This article draws on examples from the literature to highlight approaches to data analysis that exaggerate trends in data and the term correlation inflation is introduced in the context of drug discovery. Averaging groups of data points prior to analysis is a common cause of correlation inflation and results from analysis of binned continuous data should always be treated with caution.


Assuntos
Bases de Dados de Produtos Farmacêuticos , Descoberta de Drogas/métodos , Gráficos por Computador , Desenho de Fármacos , Estrutura Molecular , Solubilidade
17.
J Med Chem ; 55(20): 8827-37, 2012 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-22984809

RESUMO

Rational structure-based design has yielded highly potent inhibitors of cathepsin K (Cat K) with excellent physical properties, selectivity profiles, and pharmacokinetics. Compounds with a 3,4-(CH3O)2Ph motif, such as 31, were found to have excellent metabolic stability and absorption profiles. Through metabolite identification studies, a reactive metabolite risk was identified with this motif. Subsequent structure-based design of isoteres culminated in the discovery of an optimized and balanced inhibitor (indazole, 38).


Assuntos
Catepsina K/antagonistas & inibidores , Cicloexanos/síntese química , Indazóis/síntese química , Animais , Proteínas Sanguíneas/metabolismo , Células Cultivadas , Cicloexanos/farmacocinética , Cicloexanos/farmacologia , Desenho de Fármacos , Hepatócitos/metabolismo , Humanos , Indazóis/farmacocinética , Indazóis/farmacologia , Masculino , Modelos Moleculares , Ligação Proteica , Ratos , Ratos Wistar , Estereoisomerismo , Relação Estrutura-Atividade
18.
J Med Chem ; 55(14): 6363-74, 2012 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-22742641

RESUMO

Directed screening of nitrile compounds revealed 3 as a highly potent cathepsin K inhibitor but with cathepsin S activity and very poor stability to microsomes. Synthesis of compounds with reduced molecular complexity, such as 7, revealed key SAR and demonstrated that baseline physical properties and in vitro stability were in fact excellent for this series. The tricycle carboline P3 unit was discovered by hypothesis-based design using existing structural information. Optimization using small substituents, knowledge from matched molecular pairs, and control of lipophilicity yielded compounds very close to the desired profile, of which 34 (AZD4996) was selected on the basis of pharmacokinetic profile.


Assuntos
Carbolinas/farmacologia , Catepsina K/antagonistas & inibidores , Indóis/farmacologia , Osteoartrite/tratamento farmacológico , Inibidores de Proteases/farmacologia , Animais , Carbolinas/metabolismo , Carbolinas/farmacocinética , Carbolinas/uso terapêutico , Catepsina K/química , Cães , Humanos , Indóis/metabolismo , Indóis/farmacocinética , Indóis/uso terapêutico , Concentração Inibidora 50 , Masculino , Modelos Moleculares , Osteoartrite/enzimologia , Inibidores de Proteases/metabolismo , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/uso terapêutico , Conformação Proteica , Ratos , Especificidade por Substrato
20.
Bioorg Med Chem Lett ; 21(16): 4698-701, 2011 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-21775140

RESUMO

We disclose a novel series of insulin-like growth factor-1 receptor kinase inhibitors based on the 3-(pyrimidin-4-yl)-imidazo[1,2-a]pyridine scaffold. The influence on the inhibitory activity of substitution on the imidazopyridine and at the C5 position of the pyrimidine is discussed. In the course of this optimization, we discovered a potent and selective inhibitor with suitable pharmacokinetics for oral administration.


Assuntos
Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Cães , Humanos , Camundongos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridinas/síntese química , Piridinas/química , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Distribuição Tecidual
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