RESUMO
MOTIVATION: Gene set analysis methods rely on knowledge-based representations of genetic interactions in the form of both gene set collections and protein-protein interaction (PPI) networks. However, explicit representations of genetic interactions often fail to capture complex interdependencies among genes, limiting the analytic power of such methods. RESULTS: We propose an extension of gene set enrichment analysis to a latent embedding space reflecting PPI network topology, called gene set proximity analysis (GSPA). Compared with existing methods, GSPA provides improved ability to identify disease-associated pathways in disease-matched gene expression datasets, while improving reproducibility of enrichment statistics for similar gene sets. GSPA is statistically straightforward, reducing to a version of traditional gene set enrichment analysis through a single user-defined parameter. We apply our method to identify novel drug associations with SARS-CoV-2 viral entry. Finally, we validate our drug association predictions through retrospective clinical analysis of claims data from 8 million patients, supporting a role for gabapentin as a risk factor and metformin as a protective factor for severe COVID-19. AVAILABILITY AND IMPLEMENTATION: GSPA is available for download as a command-line Python package at https://github.com/henrycousins/gspa. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Assuntos
COVID-19 , Humanos , Reposicionamento de Medicamentos , Reprodutibilidade dos Testes , Estudos Retrospectivos , SARS-CoV-2RESUMO
The structure-activity relationship of the prime region of hydroxyethylamine BACE inhibitors is described. Variation in the aryl linker region with 5- and 6-membered heterocycles provided compounds such as 33 with improved permeability and reduced P-gp liability compared to benzyl amine analog 1.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Etilaminas/química , Etilaminas/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/química , Ácido Aspártico Endopeptidases/química , Cristalografia por Raios X , Etilaminas/síntese química , Humanos , Modelos Moleculares , Inibidores de Proteases/síntese química , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
Using structure-guided design, hydroxyethylamine BACE-1 inhibitors were optimized to nanomolar Abeta cellular inhibition with selectivity against cathepsin-D. X-ray crystallography illuminated the S1' residues critical to this effort, which culminated in compounds 56 and 57 that exhibited potency and selectivity but poor permeability and high P-gp efflux.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/química , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Desenho de Fármacos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Secretases da Proteína Precursora do Amiloide/química , Secretases da Proteína Precursora do Amiloide/genética , Ácido Aspártico Endopeptidases/química , Ácido Aspártico Endopeptidases/genética , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
The effect of ligand structure on the magnetic resonance (MR) imaging and biodistribution of six gadolinium (Gd) chelates based on a hydroxypyridonate-terephthalimide (HOPO-TAM) ligand design was investigated. Modifications to the molecular structure of the Gd-HOPO-TAM chelates (hydrophilicity and aromatic group substitution) significantly influence the efficacy of imaging and biodistribution. MR imaging was performed on female mice after intravenous (iv) injection of 100 micromol of Gd/kg of body weight of the different complexes. The biodistribution results indicate that the liver uptake of the complexes is enhanced by a short poly(ethyleneoxy) (PEO) chain, while blood pool localization is facilitated by a very long PEO chain. There is a direct correlation between the blood pool localization of the complexes and the signal intensity of blood vessels in the MRI. The imaging results are consistent with in vitro NMR measurements that indicate long PEO chains increase image enhancement capabilities in the presence of serum albumin.
Assuntos
Meios de Contraste/química , Gadolínio , Compostos Organometálicos/química , Animais , Quelantes/química , Meios de Contraste/farmacocinética , Feminino , Imidas/química , Injeções Intravenosas , Fígado/anatomia & histologia , Fígado/metabolismo , Imageamento por Ressonância Magnética , Camundongos , Compostos Organometálicos/sangue , Compostos Organometálicos/farmacocinética , Ácidos Ftálicos/química , Baço/anatomia & histologia , Baço/metabolismo , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
BACKGROUND: Osteoporosis-related fractures are a considerable economic burden on the U.S. health care system. Since 2008, the Centers for Medicare Medicaid Services have adopted a Medicare Part C Five-Star Quality Rating measure to ensure that a woman's previously unaddressed osteoporosis is managed appropriately after a fracture. Despite the effort to improve this gap in care, the 2013 CMS plan ratings fact sheet reported an average star rating of 1.4 stars for the osteoporosis measure, the lowest score for any measure across all health plans. OBJECTIVE: To evaluate the impact of conducting a pharmacist-led, telephone outreach program to members or their providers to improve osteoporosis management in elderly women after experiencing fractures. METHODS: This was a prospective, randomized study to evaluate the effectiveness of 3 different intervention strategies within a nationwide managed care population. Women aged 66 years and older who experienced a new bone fracture between January 1, 2012-August 31, 2012, were identified through medical claims. Women who were treated with an osteoporosis medication or received a bone mineral density (BMD) test within a year of their fractures were excluded. Study patients were randomized into 3 intervention cohorts: (1) baseline intervention consisting of member educational mailing and provider educational mail or fax notification; (2) baseline intervention plus a live outbound intervention call to members by a pharmacist; and (3) baseline intervention plus a pharmacist call to members' providers to recommend starting osteoporosis therapy and/or a bone mineral density (BMD) test. An intent-to-treat and per protocol analyses were employed, and appropriate osteoporosis management (initiation of osteoporosis therapy and/or BMD testing) 120 days after the baseline intervention and 180 days after a fracture were measured. RESULTS: The study identified 6,591 members who were equally randomized into 3 cohorts. The baseline demographics in each cohort were similar. Results of the intent-to-treat analysis showed more members in cohort 3 receiving appropriate osteoporosis management (13.0%) compared with those in cohort 2 (10.3%, P less than 0.005) or compared with those in cohort 1 (9.1%, P less than 0.001). No difference was detected between those receiving additional member calls (cohort 2) and those receiving only the baseline intervention (cohort 1). Similar results were observed utilizing the 180 days after fracture time frame. CONCLUSIONS: The effectiveness of a pharmacist-led telephone intervention directed at providers or members was examined in this randomized study. Pharmacist calls to members did not improve osteoporosis management over member and provider mail and fax notifications. Greater impact was demonstrated by performing a pharmacist call intervention with providers rather than with members.
Assuntos
Osteoporose/tratamento farmacológico , Fraturas por Osteoporose/prevenção & controle , Assistência Farmacêutica/organização & administração , Farmacêuticos/organização & administração , Idoso , Idoso de 80 Anos ou mais , Densidade Óssea , Conservadores da Densidade Óssea/uso terapêutico , Feminino , Humanos , Programas de Assistência Gerenciada , Osteoporose/complicações , Papel Profissional , Estudos Prospectivos , Telefone , Estados UnidosRESUMO
The synthesis and relaxometric properties of hetero-tripodal hydroxypyridonate-terephthalamide gadolinium (Gd(3+)) chelates with differing structural features for probing human serum albumin (HSA) interactions are reported. The Gd(3+) complexes are divided into two series. The first series (3-5) features a benzyl derivative connected to the hydroxypyridonate (HOPO) moiety. The second series of complexes (6-10) has the common feature of a poly(ethylene glycol) (PEG) attached to the terephthalamide (TAM) moiety and is nonbenzylated. The water exchange of the complexes is in the fast exchange regime with rates (k(ex)) in the range 0.45-1.11 x 10(8) s(-1). The complexes have a moderate interaction with HSA with association constants (K(A)'s) in the range 0.7-8.6 x 10(3) M(-1). Protein binding results in an enhancement in proton relaxivity from 7.7-10.4 mM(-1) s(-1) (r(1p)) to 15-29 mM(-1) s(-1) (r(1p)(b)). It is concluded that the interaction of the complexes with HSA (i) is enhanced by the presence of benzyl groups, (ii) is entropically driven, and (iii) results in a lower hydration number (q).