In the last few years, there have been important new insights into the structural biology of G-protein coupled receptors. It is now known that allosteric binding sites are involved in the affinity and selec- tivity of...In the last few years, there have been important new insights into the structural biology of G-protein coupled receptors. It is now known that allosteric binding sites are involved in the affinity and selec- tivity of ligands for G-protein coupled receptors, and that signaling by these receptors involves both G-protein dependent and independent pathways. The present review outlines the physiological and pharmacological implications of this perspective for the design of new drugs to treat disorders of the central nervous system. Specifically, new possibilities are explored in relation to allosteric and or- thosteric binding sites on dopamine receptors for the treatment of Parkinson＇s disease, and on muscarinic receptors for Alzheimer＇s disease. Future research can seek to identify ligands that can bind to more than one site on the same receptor, or simultaneously bind to two receptors and form a dimer. For example, the design of bivalent drugs that can reach homo/hetero-dimers of D2 dopa- mine receptor holds promise as a relevant therapeutic strategy for Parkinson＇s disease. Regarding the treatment of Alzheimer＇s disease, the design of dualsteric ligands for mono-oligomeric mus- carinic receptors could increase therapeutic effectiveness by generating potent compounds that could activate more than one signaling pathway.展开更多
目的基于生物信息学分析平台探讨龟芍平颤方抗帕金森病的分子机制。方法从1994年4月~2019年12月的中英文数据库(中国期刊全文数据库、维普期刊全文数据库、中国生物医学文献数据库、中华本草、PubMed、Web of Science、SciFinder Schol...目的基于生物信息学分析平台探讨龟芍平颤方抗帕金森病的分子机制。方法从1994年4月~2019年12月的中英文数据库(中国期刊全文数据库、维普期刊全文数据库、中国生物医学文献数据库、中华本草、PubMed、Web of Science、SciFinder Scholar)中获得龟芍平颤方(龟甲、白芍、川芎、天麻)的化学成分,并于PubChem数据库中查找该方每种有效成分的人源活性靶蛋白。检索Gene数据库,查找帕金森病相关人源基因。将上述靶蛋白与基因上传至生物信息学分析平台,分析两者共同涉及的分子网络与生物学通路。结果获得龟芍平颤方人源活性靶蛋白323个(龟甲58个、白芍119个、川芎72个、天麻74个);获取帕金森病相关人源基因392个。建立上述靶蛋白及基因共同作用的主要分子网络,并甄选出G-蛋白偶联受体信号传导通路等10条主要的生物学通路。结论龟芍平颤方可能通过调控G-蛋白偶联受体信号传导通路等发挥抗帕金森病作用。展开更多
The renal handling of Na^+ balance is a major determinant of the blood pressure(BP) level. The inability of the kidney to excrete the daily load of Na+ represents the primary cause of chronic hypertension. Among the d...The renal handling of Na^+ balance is a major determinant of the blood pressure(BP) level. The inability of the kidney to excrete the daily load of Na+ represents the primary cause of chronic hypertension. Among the different segments that constitute the nephron, those present in the distal part(i.e., the cortical thick ascending limb, the distal convoluted tubule, the connecting and collecting tubules) play a central role in the fine-tuning of renal Na^+ excretion and are the target of many different regulatory processes that modulate Na^+ retention more or less efficiently. G-protein coupled receptors(GPCRs) are crucially involved in this regulation and could represent efficient pharmacological targets to control BP levels. In this review, we describe both classical and novel GPCR-dependent regulatory systems that have been shown to modulate renal Na^+ absorption in the distal nephron. In addition to the multiplicity of the GPCR that regulate Na^+ excretion, this review also highlights the complexity of these different pathways, and the connections between them.展开更多
Octopamine regulates the function of many tissues and physiological processes in invertebrates. The expression of octopamine receptor genes has been examined in multiple tissue types in several different insect orders...Octopamine regulates the function of many tissues and physiological processes in invertebrates. The expression of octopamine receptor genes has been examined in multiple tissue types in several different insect orders. However, little work has addressed this issue in Coleoptera. Most studies characterize individual genes in different tissue types, but here we describe the expression of 6 octopamine receptor genes in thoracic musculature, oviducts, Malpighian tubules, and fat body of female Nicrophorus vespilloides beetles to characterize both different genes and different tissues within a single study. We then compare the gene expression profiles found in this beetle to other insects to examine the extent to which expression profiles are conserved across insects. We also examine the relative involvement of octopamine verses octopamine/tyramine receptors based on receptor gene expression in each tissue to help elucidate if tyramine plays a role in the regulation of these tissues. We find a high degree of overlap in the expression profile of the 6 genes examined in the thoracic muscula^tre, a moderate amount for the oviducts, and divergent profiles for Malpighian tubules and fat body. Based on expression difference in receptor subtypes, our results also support the suggestion that tyramine is a biogenic amine with physiological actions separate from octopamine.展开更多
Target identification is a critical step following the discovery of small molecules that elicit a biological phenotype. G-protein coupled recaptors (GPCRs) are among the most important drug targets for the pharmaceuti...Target identification is a critical step following the discovery of small molecules that elicit a biological phenotype. G-protein coupled recaptors (GPCRs) are among the most important drug targets for the pharmaceutical industry. The present work seeks to provide an in silico model of known GPCR protein fishing technologies in order to rapidly fish out potential drug targets on the basis of amino acid sequences and seven transmembrane regions (TMs) of GPCRs. Some scoring matrices were trained on 22 groups of GPCRs in the GPCRDB database. These models were employed to predict the GPCR proteins in two groups of test sets. On average, the mean correct rate of each TM of 38 GPCRs from two test sets (ST23 and ST24) was found 62% and 57.5%, respectively, using training set 18 (SLD18);the mean hit rate of each TM of 38 GPCRs from ST23 and ST24 was found 68.1% and 64.7%, respectively. Based on the scoring matrices of PreMod, the mean correct rate of each TM of GPCRs from ST23 and ST24 was found 62% and 62.04%, respectively;the mean hit rate of each TM of GPCRs from ST23 and ST24 was found 67.7% and 68.0%, respecttively. The means of GPCRs in ST23 based on SLD18 is close to those based on PreMod;whereas the means of GPCRs in ST24 based on?SLD18 is less than those based on PreMod. Moreover, the accuracy (“2”) and validity (“2 + 1”) rates of prediction all seven TMs of 38 GPCRs by the scoring matrices of PreMod are more than those by SLD18, SLA14 and SLA3;whereas the hit rates (94.74% and 97.37%) by PreMod are less than those of?SLA3 but bigger than those of?SLD18 and SLA14, respectively. This is the reason that we choose PreMod to predict some potential drug targets. 22 GPCR proteins in the sense chain of chromosome 19 constructing validation set were predicted and validated by PreMod whose hit rate is up to 90.91%. Further evaluation is under investigation.展开更多
基金supported by SIP-IPN,CONACYT (CB-168116)FIS/IMSS (FIS/IMSS/PROT/G11-2/1013)
文摘In the last few years, there have been important new insights into the structural biology of G-protein coupled receptors. It is now known that allosteric binding sites are involved in the affinity and selec- tivity of ligands for G-protein coupled receptors, and that signaling by these receptors involves both G-protein dependent and independent pathways. The present review outlines the physiological and pharmacological implications of this perspective for the design of new drugs to treat disorders of the central nervous system. Specifically, new possibilities are explored in relation to allosteric and or- thosteric binding sites on dopamine receptors for the treatment of Parkinson＇s disease, and on muscarinic receptors for Alzheimer＇s disease. Future research can seek to identify ligands that can bind to more than one site on the same receptor, or simultaneously bind to two receptors and form a dimer. For example, the design of bivalent drugs that can reach homo/hetero-dimers of D2 dopa- mine receptor holds promise as a relevant therapeutic strategy for Parkinson＇s disease. Regarding the treatment of Alzheimer＇s disease, the design of dualsteric ligands for mono-oligomeric mus- carinic receptors could increase therapeutic effectiveness by generating potent compounds that could activate more than one signaling pathway.
文摘目的基于生物信息学分析平台探讨龟芍平颤方抗帕金森病的分子机制。方法从1994年4月~2019年12月的中英文数据库(中国期刊全文数据库、维普期刊全文数据库、中国生物医学文献数据库、中华本草、PubMed、Web of Science、SciFinder Scholar)中获得龟芍平颤方(龟甲、白芍、川芎、天麻)的化学成分,并于PubChem数据库中查找该方每种有效成分的人源活性靶蛋白。检索Gene数据库,查找帕金森病相关人源基因。将上述靶蛋白与基因上传至生物信息学分析平台,分析两者共同涉及的分子网络与生物学通路。结果获得龟芍平颤方人源活性靶蛋白323个(龟甲58个、白芍119个、川芎72个、天麻74个);获取帕金森病相关人源基因392个。建立上述靶蛋白及基因共同作用的主要分子网络,并甄选出G-蛋白偶联受体信号传导通路等10条主要的生物学通路。结论龟芍平颤方可能通过调控G-蛋白偶联受体信号传导通路等发挥抗帕金森病作用。
文摘The renal handling of Na^+ balance is a major determinant of the blood pressure(BP) level. The inability of the kidney to excrete the daily load of Na+ represents the primary cause of chronic hypertension. Among the different segments that constitute the nephron, those present in the distal part(i.e., the cortical thick ascending limb, the distal convoluted tubule, the connecting and collecting tubules) play a central role in the fine-tuning of renal Na^+ excretion and are the target of many different regulatory processes that modulate Na^+ retention more or less efficiently. G-protein coupled receptors(GPCRs) are crucially involved in this regulation and could represent efficient pharmacological targets to control BP levels. In this review, we describe both classical and novel GPCR-dependent regulatory systems that have been shown to modulate renal Na^+ absorption in the distal nephron. In addition to the multiplicity of the GPCR that regulate Na^+ excretion, this review also highlights the complexity of these different pathways, and the connections between them.
文摘Octopamine regulates the function of many tissues and physiological processes in invertebrates. The expression of octopamine receptor genes has been examined in multiple tissue types in several different insect orders. However, little work has addressed this issue in Coleoptera. Most studies characterize individual genes in different tissue types, but here we describe the expression of 6 octopamine receptor genes in thoracic musculature, oviducts, Malpighian tubules, and fat body of female Nicrophorus vespilloides beetles to characterize both different genes and different tissues within a single study. We then compare the gene expression profiles found in this beetle to other insects to examine the extent to which expression profiles are conserved across insects. We also examine the relative involvement of octopamine verses octopamine/tyramine receptors based on receptor gene expression in each tissue to help elucidate if tyramine plays a role in the regulation of these tissues. We find a high degree of overlap in the expression profile of the 6 genes examined in the thoracic muscula^tre, a moderate amount for the oviducts, and divergent profiles for Malpighian tubules and fat body. Based on expression difference in receptor subtypes, our results also support the suggestion that tyramine is a biogenic amine with physiological actions separate from octopamine.
文摘Target identification is a critical step following the discovery of small molecules that elicit a biological phenotype. G-protein coupled recaptors (GPCRs) are among the most important drug targets for the pharmaceutical industry. The present work seeks to provide an in silico model of known GPCR protein fishing technologies in order to rapidly fish out potential drug targets on the basis of amino acid sequences and seven transmembrane regions (TMs) of GPCRs. Some scoring matrices were trained on 22 groups of GPCRs in the GPCRDB database. These models were employed to predict the GPCR proteins in two groups of test sets. On average, the mean correct rate of each TM of 38 GPCRs from two test sets (ST23 and ST24) was found 62% and 57.5%, respectively, using training set 18 (SLD18);the mean hit rate of each TM of 38 GPCRs from ST23 and ST24 was found 68.1% and 64.7%, respectively. Based on the scoring matrices of PreMod, the mean correct rate of each TM of GPCRs from ST23 and ST24 was found 62% and 62.04%, respectively;the mean hit rate of each TM of GPCRs from ST23 and ST24 was found 67.7% and 68.0%, respecttively. The means of GPCRs in ST23 based on SLD18 is close to those based on PreMod;whereas the means of GPCRs in ST24 based on?SLD18 is less than those based on PreMod. Moreover, the accuracy (“2”) and validity (“2 + 1”) rates of prediction all seven TMs of 38 GPCRs by the scoring matrices of PreMod are more than those by SLD18, SLA14 and SLA3;whereas the hit rates (94.74% and 97.37%) by PreMod are less than those of?SLA3 but bigger than those of?SLD18 and SLA14, respectively. This is the reason that we choose PreMod to predict some potential drug targets. 22 GPCR proteins in the sense chain of chromosome 19 constructing validation set were predicted and validated by PreMod whose hit rate is up to 90.91%. Further evaluation is under investigation.
