RESUMO
PDE10A is an important regulator of striatal signaling that, when inhibited, can normalize dysfunctional activity. Given the involvement of dysfunctional striatal activity with schizophrenia, PDE10A inhibition represents a potentially novel means for its treatment. With the goal of developing PDE10A inhibitors, early optimization of a fragment hit through rational design led to a series of potent pyrimidine PDE10A inhibitors that required further improvements in physicochemical properties, off-target activities, and pharmacokinetics. Herein we describe the discovery of an isomeric pyrimidine series that addresses the liabilities seen with earlier compounds and resulted in the invention of compound 18 (MK-8189), which is currently in Phase 2b clinical development for the treatment of schizophrenia.
Assuntos
Inibidores de Fosfodiesterase , Esquizofrenia , Humanos , Cristalografia por Raios X , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Inibidores de Fosfodiesterase/química , Diester Fosfórico Hidrolases/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirimidinas/química , Esquizofrenia/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
Induction of cytochrome P450 isoform 3A4 via activation of the pregnane xenobiotic receptor (PXR) is a concern for pharmaceutical discovery and development, as it can lead to drug-drug interactions. We present a novel molecular descriptor, the smallest maximum intramolecular distance (SMID), which is correlated with PXR activation, and a method for using the SMID descriptor to guide discovery chemists in modifying lead compounds to decrease PXR activation.
Assuntos
Receptores de Esteroides , Citocromo P-450 CYP3A , Interações Medicamentosas , Receptor de Pregnano X , Pregnanos , Xenobióticos/toxicidadeRESUMO
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 , TermodinâmicaRESUMO
Countless reports cite the importance of diversity in the academic, industrial, and government workplace. This article shares the different perspective on gender diversity from five women who have recently joined Vertex's computational chemistry group. It is written with the hope that other scientists will take the themes which resonant and adopt them to their own institutions to inspire the fostering of an inclusive environment while in pursuit of scientific discoveries.
Assuntos
Mobilidade Ocupacional , Química Computacional , Indústria Farmacêutica , Direitos da Mulher , Química Computacional/história , Indústria Farmacêutica/história , Feminino , História do Século XXI , Humanos , Pesquisadores/história , Direitos da Mulher/história , Local de Trabalho/históriaRESUMO
The authors were inspired to explore the topic of gender diversity in computational chemistry on the basis of similar recent publications in the related fields of medicinal chemistry ( Huryn , D. M. ; et al. ACS Med. Chem. Lett. 2017 , 8 , 900 ) and computational biology ( Bonham , K. S. ; Stefan , M. I. PLoS Comput. Biol. 2017 , 13 , e1005134 ). To do so, we examined historical demographics in two different professional settings, i.e., attendance/participation at the Gordon Research Conferences on Computer-Aided Drug Design and Computational Chemistry and membership in the Computers in Chemistry Division of the American Chemical Society. We conclude that female representation in computational chemistry has risen steadily over the last 40 years and likely stands at around 25%, which appears to slightly exceed that of the neighboring fields of computer science and medicinal chemistry. In accordance with the old slogan that "a rising tide lifts all boats", here a rising tide of women scientists is having an impact on the field of computational chemistry. Tactics to ensure that this number continues to improve are highlighted.
Assuntos
Biologia Computacional/estatística & dados numéricos , Pesquisadores/estatística & dados numéricos , Feminino , Humanos , Masculino , Distribuição por Sexo , Sociedades Científicas/organização & administraçãoRESUMO
An internal HTS effort identified a novel PDE2 inhibitor series that was subsequently optimized for improved PDE2 activity and off-target selectivity. The optimized lead, compound 4, improved cognitive performance in a rodent novel object recognition task as well as a non-human primate object retrieval task. In addition, co-crystallization studies of close analog of 4 in the PDE2 active site revealed unique binding interactions influencing the high PDE isoform selectivity.
Assuntos
Ácido Acético/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores , Indóis/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Ácido Acético/síntese química , Ácido Acético/química , Animais , Domínio Catalítico/efeitos dos fármacos , Disfunção Cognitiva/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Indóis/síntese química , Indóis/química , Estrutura Molecular , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Ratos , Relação Estrutura-AtividadeRESUMO
Molecular modelers and informaticians have the unique opportunity to integrate cross-functional data using a myriad of tools, methods and visuals to generate information. Using their drug discovery expertise, information is transformed to knowledge that impacts drug discovery. These insights are often times formulated locally and then applied more broadly, which influence the discovery of new medicines. This is particularly true in an organization where the members are exposed to projects throughout an organization, such as in the case of the global Modeling & Informatics group at Vertex Pharmaceuticals. From its inception, Vertex has been a leader in the development and use of computational methods for drug discovery. In this paper, we describe the Modeling & Informatics group at Vertex and the underlying philosophy, which has driven this team to sustain impact on the discovery of first-in-class transformative medicines.
Assuntos
Desenho Assistido por Computador , Descoberta de Drogas , Indústria Farmacêutica/métodos , Química Farmacêutica , Biologia Computacional , Desenho de Fármacos , Modelos Moleculares , Software , Relação Estrutura-AtividadeRESUMO
In May and August, 2016, several pharmaceutical companies convened to discuss and compare experiences with Free Energy Perturbation (FEP). This unusual synchronization of interest was prompted by Schrödinger's FEP+ implementation and offered the opportunity to share fresh studies with FEP and enable broader discussions on the topic. This article summarizes key conclusions of the meetings, including a path forward of actions for this group to aid the accelerated evaluation, application and development of free energy and related quantitative, structure-based design methods.
Assuntos
Descoberta de Drogas/métodos , Preparações Farmacêuticas/química , Desenho de Fármacos , Indústria Farmacêutica , Humanos , Estrutura Molecular , Software , Relação Estrutura-Atividade , TermodinâmicaRESUMO
Three (3) different methods (logistic regression, covariate shift and k-NN) were applied to five (5) internal datasets and one (1) external, publically available dataset where covariate shift existed. In all cases, k-NN's performance was inferior to either logistic regression or covariate shift. Surprisingly, there was no obvious advantage for using covariate shift to reweight the training data in the examined datasets.
RESUMO
We benchmarked the ability of comparative computational approaches to correctly discriminate protein pairs sharing a common active ligand (positive protein pairs) from protein pairs with no common active ligands (negative protein pairs). Since the target and the off-targets of a drug share at least a common ligand, i.e., the drug itself, the prediction of positive protein pairs may help identify off-targets. We evaluated representative protein-centric and ligand-centric approaches, including (1) 2D and 3D ligand similarity, (2) several measures of protein sequence similarity in conjunction with different sequence sources (e.g., full protein sequence versus binding site residues), and (3) a newly described pocket shape similarity and alignment program called SiteHopper. While the sequence-based alignment of pocket residues achieved the best overall performance, SiteHopper outperformed sequence-based approaches for unrelated proteins with only 20-30% pocket residue identity. Analogously, among ligand-centric approaches, path-based fingerprints achieved the best overall performance, but ROCS-based ligand shape similarity outperformed path-based fingerprints for structurally dissimilar ligands (Tanimoto 25%-40%). A significant drop in recognition performance was observed for ligand-centric approaches when PDB ligands were used instead of ChEMBL ligands. Finally, we analyzed the relationship between pocket shape and ligand shape in our data set and found that similar ligands tend to bind to similar pockets while similar pockets may accept a range of different-shaped ligands.
Assuntos
Biologia Computacional , Proteínas/química , Proteínas/metabolismo , Sequência de Aminoácidos , Benchmarking , Ligantes , Modelos Moleculares , Conformação ProteicaRESUMO
Herein, we present the identification of a novel class of pyrazolopyrimidine phosphodiesterase 10A (PDE10A) inhibitors. Beginning with a lead molecule (1) identified through a fragment-based drug discovery (FBDD) effort, lead optimization was enabled by rational design, X-ray crystallography, metabolic and off-target profiling, and fragment scaffold-hopping. We highlight the discovery of PyP-1, a potent, highly selective, and orally bioavailable pyrazolopyrimidine inhibitor of PDE10A. PyP-1 exhibits sub-nanomolar potency (PDE10A Ki=0.23nM), excellent pharmacokinetic (PK) and physicochemical properties, and a clean off-target profile. It displays dose-dependent efficacy in numerous pharmacodynamic (PD) assays that measure potential for anti-psychotic activity and cognitive improvement. PyP-1 also has a clean preclinical profile with respect to cataleptic potential in rats, prolactin secretion, and weight gain, common adverse events associated with currently marketed therapeutics. Further, PyP-1 displays in vivo preclinical target engagement as measured by PET enzyme occupancy in concert with [(11)C]MK-8193, a novel PDE10A PET tracer.
Assuntos
Descoberta de Drogas , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Esquizofrenia/tratamento farmacológico , Animais , Cristalografia por Raios X , Cães , Relação Dose-Resposta a Droga , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Humanos , Macaca mulatta , Modelos Moleculares , Estrutura Molecular , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Ratos , Ratos Wistar , Esquizofrenia/enzimologia , Relação Estrutura-AtividadeRESUMO
Screening of a fragment library for PDE10A inhibitors identified a low molecular weight pyrimidine hit with PDE10A Ki of 8700 nM and LE of 0.59. Initial optimization by catalog followed by iterative parallel synthesis guided by X-ray cocrystal structures resulted in rapid potency improvements with minimal loss of ligand efficiency. Compound 15 h, with PDE10A Ki of 8.2 pM, LE of 0.49, and >5000-fold selectivity over other PDEs, fully attenuates MK-801-induced hyperlocomotor activity after ip dosing.
Assuntos
Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Relação Estrutura-Atividade , Animais , Técnicas de Química Sintética , Cristalografia por Raios X , Modelos Animais de Doenças , Maleato de Dizocilpina/farmacologia , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Masculino , Inibidores de Fosfodiesterase/síntese química , Diester Fosfórico Hidrolases/química , Diester Fosfórico Hidrolases/metabolismo , Pirimidinas/química , Ratos Wistar , Esquizofrenia/tratamento farmacológicoRESUMO
The IC50 of a beta-secretase (BACE-1) lead compound was improved â¼200-fold from 11 µM to 55 nM through the addition of a single methyl group. Computational chemistry, small molecule NMR, and protein crystallography capabilities were used to compare the solution conformation of the ligand under varying pH conditions to its conformation when bound in the active site. Chemical modification then explored available binding pockets adjacent to the ligand. A strategically placed methyl group not only maintained the required pKa of the piperidine nitrogen and filled a small hydrophobic pocket, but more importantly, stabilized the conformation best suited for optimized binding to the receptor.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Hidantoínas/química , Hidantoínas/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Hidantoínas/síntese química , Metilação , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Phosphodiesterase 10A (PDE10A) inhibition has recently been identified as a potential mechanism to treat multiple symptoms that manifest in schizophrenia. In order to facilitate preclinical development and support key proof-of-concept clinical trials of novel PDE10A inhibitors, it is critical to discover positron emission tomography (PET) tracers that enable plasma concentration/PDE10A occupancy relationships to be established across species with structurally diverse PDE10A inhibitors. In this Letter, we describe how a high-throughput screening hit was optimized to provide [(11)C]MK-8193 (8j), a PET tracer that supports the determination of plasma concentration/PDE10A occupancy relationships for structurally diverse series of PDE10A inhibitors in both rat and rhesus monkey.
Assuntos
Descoberta de Drogas , Compostos Heterocíclicos com 2 Anéis/química , Inibidores de Fosfodiesterase/metabolismo , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Tomografia por Emissão de Pósitrons , Animais , Encéfalo/metabolismo , Radioisótopos de Carbono , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Compostos Heterocíclicos com 2 Anéis/síntese química , Macaca mulatta , Modelos Moleculares , Estrutura Molecular , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Diester Fosfórico Hidrolases/sangue , Ratos , Relação Estrutura-AtividadeRESUMO
Dual Orexin Receptor Antagonists (DORA) bind to both the Orexin 1 and 2 receptors. High resolution crystal structures of the Orexin 1 and 2 receptors, both class A GPCRs, were not available at the time of this study, and thus, ligand-based analyses were invoked and successfully applied to the design of DORAs. Computational analysis, ligand based superposition, unbound small-molecule X-ray crystal structures and NMR analysis were utilized to understand the conformational preferences of key DORAs and excellent agreement between these orthogonal approaches was seen in the majority of compounds examined. The predominantly face-to-face (F2F) interaction observed between the distal aromatic rings was the core 3D shape motif in our design principle and was used in the development of compounds. A notable exception, however, was seen between computation and experiment for suvorexant where the molecule exhibits an extended conformation in the unbound small-molecule X-ray structure. Even taking into account solvation effects explicitly in our calculations, we nevertheless find support that the F2F conformation is the bioactive conformation. Using a dominant states approximation for the partition function, we made a comprehensive assessment of the free energies required to adopt both an extended and a F2F conformation of a number of DORAs. Interestingly, we find that only a F2F conformation is consistent with the activities reported.
Assuntos
Azepinas/química , Cristalografia por Raios X , Receptores de Orexina/química , Triazóis/química , Humanos , Ligantes , Espectroscopia de Ressonância Magnética , Conformação Molecular , Estrutura Molecular , Antagonistas dos Receptores de OrexinaRESUMO
We describe the discovery of potent and orally bioavailable tetrahydropyridopyrimidine inhibitors of phosphodiesterase 10A by systematic optimization of a novel HTS lead. Lead compound THPP-1 exhibits nanomolar potencies, excellent pharmacokinetic properties, and a clean off-target profile. It displays in vivo target engagement as measured by increased rat striatal cGMP levels upon oral dosing. It shows dose-dependent efficacy in a key pharmacodynamic assay predictive of antipsychotic activity, the psychostimulant-induced rat hyperlocomotion assay. Further, THPP-1 displays significantly fewer preclinical adverse events in assays measuring prolactin secretion, catalepsy, and weight gain, in contrast to the typical and atypical antipsychotics haloperidol and olanzapine.
Assuntos
Descoberta de Drogas , Inibidores de Fosfodiesterase/uso terapêutico , Piridinas/farmacologia , Pirimidinas/farmacologia , Esquizofrenia/tratamento farmacológico , Administração Oral , Animais , GMP Cíclico/análise , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Inibidores de Fosfodiesterase/administração & dosagem , Inibidores de Fosfodiesterase/química , Diester Fosfórico Hidrolases/metabolismo , Piridinas/administração & dosagem , Piridinas/química , Pirimidinas/administração & dosagem , Pirimidinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
MK-6186 is a novel nonnucleoside reverse transcriptase inhibitor (NNRTI) which displays subnanomolar potency against wild-type (WT) virus and the two most prevalent NNRTI-resistant RT mutants (K103N and Y181C) in biochemical assays. In addition, it showed excellent antiviral potency against K103N and Y181C mutant viruses, with fold changes (FCs) of less than 2 and 5, respectively. When a panel of 12 common NNRTI-associated mutant viruses was tested with MK-6186, only 2 relatively rare mutants (Y188L and V106I/Y188L) were highly resistant, with FCs of >100, and the remaining viruses showed FCs of <10. Furthermore, a panel of 96 clinical virus isolates with NNRTI resistance mutations was evaluated for susceptibility to NNRTIs. The majority (70%) of viruses tested displayed resistance to efavirenz (EFV), with FCs of >10, whereas only 29% of the mutant viruses displayed greater than 10-fold resistance to MK-6186. To determine whether MK-6186 selects for novel resistance mutations, in vitro resistance selections were conducted with one isolate each from subtypes A, B, and C under low-multiplicity-of-infection (MOI) conditions. The results showed a unique mutation development pattern in which L234I was the first mutation to emerge in the majority of the experiments. In resistance selection under high-MOI conditions with subtype B virus, V106A was the dominant mutation detected in the breakthrough viruses. More importantly, mutant viruses selected by MK-6186 showed FCs of <10 against EFV or etravirine (ETR), and the mutant viruses containing mutations selected by EFV or ETR were sensitive to MK-6186 (FCs of <10).
Assuntos
Fármacos Anti-HIV/farmacologia , HIV-1/enzimologia , Inibidores da Transcriptase Reversa/farmacologia , Alcinos , Benzoxazinas/farmacologia , Ciclopropanos , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/genética , HIV-1/genética , MutaçãoRESUMO
Insomnia is a common disorder that can be comorbid with other physical and psychological illnesses. Traditional management of insomnia relies on general central nervous system (CNS) suppression using GABA modulators. Many of these agents fail to meet patient needs with respect to sleep onset, maintenance, and next-day residual effects and have issues related to tolerance, memory disturbances, and balance. Orexin neuropeptides are central regulators of wakefulness, and orexin antagonism has been identified as a novel mechanism for treating insomnia with clinical proof of concept. Herein we describe the discovery of a series of α-methylpiperidine carboxamide dual orexinâ 1 and orexinâ 2 receptor (OX(1) R/OX(2) R) antagonists (DORAs). The design of these molecules was inspired by earlier work from this laboratory in understanding preferred conformational properties for potent orexin receptor binding. Minimization of 1,3-allylic strain interactions was used as a design principle to synthesize 2,5-disubstituted piperidine carboxamides with axially oriented substituents including DORA 28. DORA 28 (MK-6096) has exceptional inâ vivo activity in preclinical sleep models, and has advanced into phaseâ II clinical trials for the treatment of insomnia.
Assuntos
Hipnóticos e Sedativos/síntese química , Piperidinas/síntese química , Piridinas/síntese química , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Triazóis/síntese química , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cães , Descoberta de Drogas , Humanos , Hipnóticos e Sedativos/farmacocinética , Hipnóticos e Sedativos/farmacologia , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Receptores de Orexina , Piperidinas/farmacocinética , Piperidinas/farmacologia , Ligação Proteica , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/metabolismo , Sono , Distúrbios do Início e da Manutenção do Sono/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/farmacocinética , Triazóis/farmacologia , Vigília/efeitos dos fármacosRESUMO
We have developed a novel series of pyrrolidine derived BACE-1 inhibitors. The potency of the weak initial lead structure was enhanced using library-based SAR methods. The series was then further advanced by rational design while maintaining a minimal ligand binding efficiency threshold. Ultimately, the co-crystal structure was obtained revealing that these inhibitors interacted with the enzyme in a unique fashion. In all, the potency of the series was enhanced by 4 orders of magnitude from the HTS lead with concomitant increases in physical properties needed for series advancement. The progression of these developments in a systematic fashion is described.
Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Química Farmacêutica/métodos , Pirrolidinas/farmacologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Cristalização , Cristalografia por Raios X/métodos , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Concentração Inibidora 50 , Ligantes , Modelos Químicos , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
Next generation NNRTIs are sought which possess both broad spectrum antiviral activity against key mutant strains and a high genetic barrier to the selection of new mutant viral strains. Pyridones were evaluated as an acyclic conformational constraint to replace the aryl ether core of MK-4965 (1) and the more rigid indazole constraint of MK-6186 (2). The resulting pyridone compounds are potent inhibitors of HIV RT and have antiviral activity in cell culture that is superior to other next generation NNRTI's.