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1.
J Chem Inf Model ; 60(9): 4116-4119, 2020 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-32026691

RESUMO

Virtual screening is no longer merely a matter of identifying the subset of compounds from a large collection likely to be active against a particular endpoint. This viewpoint shares some distinctive practices at Novartis, where virtual screening combines multiple computational tools that marry the competing goals of biasing the selection of compounds toward multiple desired properties, while diversifying the selection to sample the available chemistry space, identifying quality compounds that inform drug discovery. Topics include the various considerations needed for a successful virtual screening practice: triaging, compound quality, accuracy and test sets, activity prediction including multitask modeling, virtual profiling, automation, multiproperty bias, diversity and property spaces, and biased-diversity designs.


Assuntos
Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos
2.
J Comput Aided Mol Des ; 34(2): 99-119, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31974851

RESUMO

The Drug Design Data Resource (D3R) aims to identify best practice methods for computer aided drug design through blinded ligand pose prediction and affinity challenges. Herein, we report on the results of Grand Challenge 4 (GC4). GC4 focused on proteins beta secretase 1 and Cathepsin S, and was run in an analogous manner to prior challenges. In Stage 1, participant ability to predict the pose and affinity of BACE1 ligands were assessed. Following the completion of Stage 1, all BACE1 co-crystal structures were released, and Stage 2 tested affinity rankings with co-crystal structures. We provide an analysis of the results and discuss insights into determined best practice methods.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Inibidores Enzimáticos/química , Humanos , Ligantes , Aprendizado de Máquina , Simulação de Acoplamento Molecular , Bibliotecas de Moléculas Pequenas/química , Termodinâmica
3.
J Chem Inf Model ; 59(5): 1709-1714, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-30943027

RESUMO

The success of hit-finding campaigns relies on many factors, including the quality and diversity of the set of compounds that is selected for screening. This paper presents a generalized workflow that guides compound selections from large compound archives with opportunities to bias the selections with available knowledge in order to improve hit quality while still effectively sampling the accessible chemical space. An optional flag in the workflow supports an explicit complement design function where diversity selections complement a given core set of compounds. Results from three project applications as well as a literature case study exemplify the effectiveness of the approach, which is available as a KNIME workflow named Biased Complement Diversity (BCD).


Assuntos
Descoberta de Drogas/métodos , Animais , Antibacterianos/farmacologia , Antimaláricos/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Ensaios de Triagem em Larga Escala/métodos , Humanos , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Mapas de Interação de Proteínas/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Fluxo de Trabalho
5.
Bioorg Med Chem Lett ; 22(4): 1678-81, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22264479

RESUMO

Compounds belonging to several scaffolds-quinazolines, quinolines and quinoxalines-were designed and synthesized as Raf kinase inhibitors. Scaffolds were assessed for in vitro Braf(V600E) inhibition, and overall kinase selectivity. Pharmacokinetic parameters for one of the scaffolds were also determined.


Assuntos
Amidas/síntese química , Amidas/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Quinases raf/antagonistas & inibidores , Amidas/química , Sítios de Ligação , Células Cultivadas , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Modelos Moleculares , Estrutura Molecular
6.
ACS Omega ; 7(6): 5401-5414, 2022 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-35187355

RESUMO

The continuing emergence of antibacterial resistance reduces the effectiveness of antibiotics and drives an ongoing search for effective replacements. Screening compound libraries for antibacterial activity in standard growth media has been extensively explored and may be showing diminishing returns. Inhibition of bacterial targets that are selectively important under in vivo (infection) conditions and, therefore, would be missed by conventional in vitro screens might be an alternative. Surrogate host models of infection, however, are often not suitable for high-throughput screens. Here, we adapted a medium-throughput Tetrahymena pyriformis surrogate host model that was successfully used to identify inhibitors of a hyperviscous Klebsiella pneumoniae strain to a high-throughput format and screened circa 1.2 million compounds. The screen was robust and identified confirmed hits from different chemical classes with potent inhibition of K. pneumoniae growth in the presence of T. pyriformis that lacked any appreciable direct antibacterial activity. Several of these appeared to inhibit capsule/mucoidy, which are key virulence factors in hypervirulent K. pneumoniae. A weakly antibacterial inhibitor of LpxC (essential for the synthesis of the lipid A moiety of lipopolysaccharides) also appeared to be more active in the presence of T. pyriformis, which is consistent with the role of LPS in virulence as well as viability in K. pneumoniae.

7.
Nat Rev Chem ; 6(4): 287-295, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35783295

RESUMO

One aspirational goal of computational chemistry is to predict potent and drug-like binders for any protein, such that only those that bind are synthesized. In this Roadmap, we describe the launch of Critical Assessment of Computational Hit-finding Experiments (CACHE), a public benchmarking project to compare and improve small molecule hit-finding algorithms through cycles of prediction and experimental testing. Participants will predict small molecule binders for new and biologically relevant protein targets representing different prediction scenarios. Predicted compounds will be tested rigorously in an experimental hub, and all predicted binders as well as all experimental screening data, including the chemical structures of experimentally tested compounds, will be made publicly available, and not subject to any intellectual property restrictions. The ability of a range of computational approaches to find novel binders will be evaluated, compared, and openly published. CACHE will launch 3 new benchmarking exercises every year. The outcomes will be better prediction methods, new small molecule binders for target proteins of importance for fundamental biology or drug discovery, and a major technological step towards achieving the goal of Target 2035, a global initiative to identify pharmacological probes for all human proteins.

9.
Nat Rev Drug Discov ; 19(5): 353-364, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31801986

RESUMO

Artificial intelligence (AI) tools are increasingly being applied in drug discovery. While some protagonists point to vast opportunities potentially offered by such tools, others remain sceptical, waiting for a clear impact to be shown in drug discovery projects. The reality is probably somewhere in-between these extremes, yet it is clear that AI is providing new challenges not only for the scientists involved but also for the biopharma industry and its established processes for discovering and developing new medicines. This article presents the views of a diverse group of international experts on the 'grand challenges' in small-molecule drug discovery with AI and the approaches to address them.


Assuntos
Inteligência Artificial , Desenho de Fármacos , Descoberta de Drogas/métodos , Humanos
10.
ACS Infect Dis ; 5(10): 1688-1692, 2019 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-31478369

RESUMO

Monobactam antibiotic 1 is active against Gram-negative bacteria even though it has a higher molecular weight (MW) than the limit of 600 Da typically applied in designing such compounds. On the basis of 2D NMR data, the compound is able to adopt a compact conformation. The dimensions, projection area, and dipole moment derived from this conformation are compatible with porin permeation, as are locations of polar groups upon superimposition to the crystal structure of ampicillin bound to E. coli OmpF porin. Minimum inhibitory concentration (MIC) shifts in a porin knock-out strain are also consistent with 1 predominately permeating through porins. In conclusion, we describe a carefully characterized case of a molecule outside default design parameters where MW does not adequately represent the 3D shape more directly related to permeability. Leveraging 3D design criteria would open up additional chemical space currently underutilized due to limitations perceived in 2D.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Monobactamas/química , Monobactamas/farmacologia , Escherichia coli/efeitos dos fármacos , Proteínas de Escherichia coli/efeitos dos fármacos , Interações Hidrofóbicas e Hidrofílicas , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Peso Molecular , Permeabilidade , Porinas
11.
Cell Chem Biol ; 25(11): 1327-1336.e4, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30122370

RESUMO

KRAS is frequently mutated in several of the most lethal types of cancer; however, the KRAS protein has proven a challenging drug target. K-RAS4B must be localized to the plasma membrane by prenylation to activate oncogenic signaling, thus we endeavored to target the protein-membrane interface with small-molecule compounds. While all reported lead compounds have low affinity for KRAS in solution, the potency of Cmpd2 was strongly enhanced when prenylated K-RAS4B is associated with a lipid bilayer. We have elucidated a unique mechanism of action of Cmpd2, which simultaneously engages a shallow pocket on KRAS and associates with the lipid bilayer, thereby stabilizing KRAS in an orientation in which the membrane occludes its effector-binding site, reducing RAF binding and impairing activation of RAF. Furthermore, enrichment of Cmpd2 on the bilayer enhances potency by promoting interaction with KRAS. This insight reveals a novel approach to developing inhibitors of membrane-associated proteins.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Animais , Descoberta de Drogas , Humanos , Indóis/química , Indóis/farmacologia , Bicamadas Lipídicas/metabolismo , Modelos Moleculares , Proteínas Proto-Oncogênicas p21(ras)/química , Proteínas Proto-Oncogênicas p21(ras)/metabolismo
12.
F1000Res ; 6: 1136, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28928948

RESUMO

The first challenge in the 2014 competition launched by the Teach-Discover-Treat (TDT) initiative asked for the development of a tutorial for ligand-based virtual screening, based on data from a primary phenotypic high-throughput screen (HTS) against malaria. The resulting Workflows were applied to select compounds from a commercial database, and a subset of those were purchased and tested experimentally for anti-malaria activity. Here, we present the two most successful Workflows, both using machine-learning approaches, and report the results for the 114 compounds tested in the follow-up screen. Excluding the two known anti-malarials quinidine and amodiaquine and 31 compounds already present in the primary HTS, a high hit rate of 57% was found.

13.
J Med Chem ; 60(20): 8482-8514, 2017 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-29016121

RESUMO

In an effort to identify new antidiabetic agents, we have discovered a novel family of (5-imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine analogues which are inhibitors of human glycogen synthase kinase 3 (GSK3). We developed efficient synthetic routes to explore a wide variety of substitution patterns and convergently access a diverse array of analogues. Compound 1 (CHIR-911, CT-99021, or CHIR-73911) emerged from an exploration of heterocycles at the C-5 position, phenyl groups at C-4, and a variety of differently substituted linker and aminopyridine moieties attached at the C-2 position. These compounds exhibited GSK3 IC50s in the low nanomolar range and excellent selectivity. They activate glycogen synthase in insulin receptor-expressing CHO-IR cells and primary rat hepatocytes. Evaluation of lead compounds 1 and 2 (CHIR-611 or CT-98014) in rodent models of type 2 diabetes revealed that single oral doses lowered hyperglycemia within 60 min, enhanced insulin-stimulated glucose transport, and improved glucose disposal without increasing insulin levels.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Quinases da Glicogênio Sintase/antagonistas & inibidores , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Pirimidinas/farmacologia , Animais , Células CHO , Cromatografia Líquida de Alta Pressão , Cricetulus , Cristalografia por Raios X , Inibidores Enzimáticos/metabolismo , Humanos , Hipoglicemiantes/metabolismo , Espectrometria de Massas , Espectroscopia de Prótons por Ressonância Magnética , Pirimidinas/química , Pirimidinas/metabolismo , Ratos , Relação Estrutura-Atividade
14.
J Med Chem ; 60(12): 4869-4881, 2017 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-28557458

RESUMO

RAS oncogenes have been implicated in >30% of human cancers, all representing high unmet medical need. The exquisite dependency on CRAF kinase in KRAS mutant tumors has been established in genetically engineered mouse models and human tumor cells. To date, many small molecule approaches are under investigation to target CRAF, yet kinase-selective and cellular potent inhibitors remain challenging to identify. Herein, we describe 14 (RAF709) [ Aversa , Biaryl amide compounds as kinase inhibitors and their preparation . WO 2014151616, 2014 ], a selective B/C RAF inhibitor, which was developed through a hypothesis-driven approach focusing on drug-like properties. A key challenge encountered in the medicinal chemistry campaign was maintaining a balance between good solubility and potent cellular activity (suppression of pMEK and proliferation) in KRAS mutant tumor cell lines. We investigated the small molecule crystal structure of lead molecule 7 and hypothesized that disruption of the crystal packing would improve solubility, which led to a change from N-methylpyridone to a tetrahydropyranyl oxy-pyridine derivative. 14 proved to be soluble, kinase selective, and efficacious in a KRAS mutant xenograft model.


Assuntos
2,2'-Dipiridil/análogos & derivados , Antineoplásicos/farmacologia , Benzamidas/farmacologia , Quinases raf/antagonistas & inibidores , Proteínas ras/genética , 2,2'-Dipiridil/química , 2,2'-Dipiridil/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Benzamidas/química , Cristalografia por Raios X , Cães , Desenho de Fármacos , Descoberta de Drogas , Estabilidade de Medicamentos , Humanos , Concentração Inibidora 50 , Camundongos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/genética , Proteínas Proto-Oncogênicas B-raf/química , Proteínas Proto-Oncogênicas p21(ras)/genética , Ratos , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
15.
PLoS One ; 12(4): e0174706, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28384226

RESUMO

RAS mutations lead to a constitutively active oncogenic protein that signals through multiple effector pathways. In this chemical biology study, we describe a novel coupled biochemical assay that measures activation of the effector BRAF by prenylated KRASG12V in a lipid-dependent manner. Using this assay, we discovered compounds that block biochemical and cellular functions of KRASG12V with low single-digit micromolar potency. We characterized the structural basis for inhibition using NMR methods and showed that the compounds stabilized the inactive conformation of KRASG12V. Determination of the biophysical affinity of binding using biolayer interferometry demonstrated that the potency of inhibition matches the affinity of binding only when KRAS is in its native state, namely post-translationally modified and in a lipid environment. The assays we describe here provide a first-time alignment across biochemical, biophysical, and cellular KRAS assays through incorporation of key physiological factors regulating RAS biology, namely a negatively charged lipid environment and prenylation, into the in vitro assays. These assays and the ligands we discovered are valuable tools for further study of KRAS inhibition and drug discovery.


Assuntos
Lipídeos/química , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Animais , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Espectroscopia de Ressonância Magnética , Prenilação
16.
Curr Opin Chem Biol ; 8(4): 359-64, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15288244

RESUMO

Structure-based virtual screening followed by selection of a top fraction of the rank-ordered result list suffers from many false positives and false negatives because the general scoring functions are not accurate enough. Many approaches have emerged to address this problem by including knowledge about the specific target in the scoring and selection steps. This target bias can include requirements for critical interactions, use of pharmacophore patterns or interaction patterns found in known co-crystal structures, and similarity to known ligands. Such biases are implemented in methods that vary from filtering tools for pre- or post-processing, to expert systems, quantitative (re)scoring functions, and docking tools that generate target-biased poses.


Assuntos
Desenho Assistido por Computador , Desenho de Fármacos , Sistemas Inteligentes , Proteínas/química , Algoritmos , Sítios de Ligação , Ligantes , Relação Estrutura-Atividade
17.
J Mol Graph Model ; 38: 360-2, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23085175

RESUMO

Teach-Discover-Treat (TDT) is an initiative to promote the development and sharing of computational tools solicited through a competition with the aim to impact education and collaborative drug discovery for neglected diseases. Collaboration, multidisciplinary integration, and innovation are essential for successful drug discovery. This requires a workforce that is trained in state-of-the-art workflows and equipped with the ability to collaborate on platforms that are accessible and free. The TDT competition solicits high quality computational workflows for neglected disease targets, using freely available, open access tools.


Assuntos
Descoberta de Drogas/métodos , Comunicação Interdisciplinar , Simulação de Dinâmica Molecular , Software , Comportamento Cooperativo , Descoberta de Drogas/organização & administração , Humanos , Doenças Negligenciadas/tratamento farmacológico , Recursos Humanos
18.
J Med Chem ; 52(2): 278-92, 2009 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-19113866

RESUMO

The inhibition of key receptor tyrosine kinases (RTKs) that are implicated in tumor vasculature formation and maintenance, as well as tumor progression and metastasis, has been a major focus in oncology research over the last several years. Many potent small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases have been evaluated. More recently, compounds that act through the complex inhibition of multiple kinase targets have been reported and may exhibit improved clinical efficacy. We report herein a series of potent, orally efficacious 4-amino-3-benzimidazol-2-ylhydroquinolin-2-one analogues as inhibitors of VEGF, PDGF, and fibroblast growth factor (FGF) receptor tyrosine kinases. Compounds in this class, such as 5 (TKI258), are reversible ATP-competitive inhibitors of VEGFR-2, FGFR-1, and PDGFRbeta with IC(50) values <0.1 microM. On the basis of its favorable in vitro and in vivo properties, compound 5 was selected for clinical evaluation and is currently in phase I clinical trials.


Assuntos
Desenho de Fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Quinolonas/química , Quinolonas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Animais , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Modelos Moleculares , Inibidores de Proteínas Quinases/farmacocinética , Quinolonas/farmacocinética , Relação Estrutura-Atividade
19.
J Med Chem ; 51(22): 7049-52, 2008 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-18942827
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