Journal of drug design and research最新文献

Exploring Modifications of an HIV-1 Capsid Inhibitor: Design, Synthesis, and Mechanism of Action. 探索修饰HIV-1衣壳抑制剂:设计、合成和作用机制。

Journal of drug design and research Pub Date : 2018-01-01 Epub Date: 2018-08-13

Jimmy P Xu, Ashwanth C Francis, Megan E Meuser, Marie Mankowski, Roger G Ptak, Adel A Rashad, Gregory B Melikyan, Simon Cocklin

{"title":"Exploring Modifications of an HIV-1 Capsid Inhibitor: Design, Synthesis, and Mechanism of Action.","authors":"Jimmy P Xu, Ashwanth C Francis, Megan E Meuser, Marie Mankowski, Roger G Ptak, Adel A Rashad, Gregory B Melikyan, Simon Cocklin","doi":"","DOIUrl":"","url":null,"abstract":"Recent efforts by both academic and pharmaceutical researchers have focused on the HIV-1 capsid (CA) protein as a new therapeutic target. An interprotomer pocket within the hexamer configuration of the CA, which is also a binding site for key host dependency factors, is the target of the most widely studied CA inhibitor compound PF-3450074 (PF-74). Despite its popularity, PF-74 suffers from properties that limit its usefulness as a lead, most notably it's extremely poor metabolic stability. To minimize unfavorable qualities, we investigated bioisosteric modification of the PF-74 scaffold as a first step in redeveloping this compound. Using a field-based bioisostere identification method, coupled with biochemical and biological assessment, we have created four new compounds that inhibit HIV-1 infection and that bind to the assembled CA hexamer. Detailed mechanism of action studies indicates that the modifications alter the manner in which these new compounds affect HIV-1 capsid core stability, as compared to the parental compound. Further investigations are underway to redevelop these compounds to optimize potency and drug-like characteristics and to deeply define the mechanism of action.","PeriodicalId":90892,"journal":{"name":"Journal of drug design and research","volume":"5 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214487/pdf/nihms-985936.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36647394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sex Differences in the Motivational Contrast between Sucrose and Cocaine in Rats. 蔗糖和可卡因对大鼠动机对比的性别差异。

Journal of drug design and research Pub Date : 2017-01-01 Epub Date: 2017-03-28

Udita Datta, Mariangela Martini, Wen Lin Sun

{"title":"Sex Differences in the Motivational Contrast between Sucrose and Cocaine in Rats.","authors":"Udita Datta, Mariangela Martini, Wen Lin Sun","doi":"","DOIUrl":"","url":null,"abstract":"There are sex differences in the vulnerability to cocaine abuse and addiction. Understanding the differences is critical for developing the sex-tailored prevention and treatment strategies. Cocaine addiction is characterized by the pathological motivation for cocaine accompanied by the diminished motivation for natural rewards. Thus, the motivational impact of cocaine relative to natural rewards likely determines the attractiveness of cocaine and likely plays a role in the vulnerability to cocaine abuse and addiction. This study aimed to determine whether the relative magnitudes or contrast of the motivational impact between cocaine and sucrose is different between sexes. To this end, cocaine-naïve out bred Wistar rats were trained to self-administer sucrose pellets and the motivation for different amounts of sucrose was then determined as the breakpoints under the progressive-ratio schedule of reinforcement. Following the sucrose tests, the same rats were trained to self-administer cocaine and the motivation for different doses of cocaine was similarly measured. For the female rats, the motivation was also measured during the diestrus and proestrus/estrus, respectively, to determine the impact of the estrous cycle on the motivational effects of cocaine and sucrose. The differences between the breakpoints of cocaine and sucrose were significantly larger in the males. The enhanced motivational contrast may contribute to the increased vulnerability to recreational cocaine abuse and addiction in the males.","PeriodicalId":90892,"journal":{"name":"Journal of drug design and research","volume":"4 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494449/pdf/nihms-1632212.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39499085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Epigenetic Basis of Clozapine Action. 氯氮平作用的表观遗传学基础。

Journal of drug design and research Pub Date : 2017-01-01 Epub Date: 2017-06-29

Guidotti Alessandro, Dong Erbo, Dennis R Grayson

引用次数: 0

Tissue Plasminogen Activator: Side Effects and Signaling. 组织纤溶酶原激活剂:副作用和信号传导。

Journal of drug design and research Pub Date : 2014-09-25

Ling Lin, Kebin Hu

引用次数: 0