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11.
Algirdas Mikalkėnas Bazilė Ravoitytė Daiva Tauraitė Elena Servienė Rolandas Meškys 《Journal of enzyme inhibition and medicinal chemistry》2018,33(1):384-389
Small molecule inhibitors have a powerful blocking action on viral polymerases. The bioavailability of the inhibitor, nevertheless, often raise a significant selectivity constraint and may substantially limit the efficacy of therapy. Phosphonoacetic acid has long been known to possess a restricted potential to block DNA biosynthesis. In order to achieve a better affinity, this compound has been linked with natural nucleotide at different positions. The structural context of the resulted conjugates has been found to be crucial for the acquisition by DNA polymerases. We show that nucleobase-conjugated phosphonoacetic acid is being accepted, but this alters the processivity of DNA polymerases. The data presented here not only provide a mechanistic rationale for a switch in the mode of DNA synthesis, but also highlight the nucleobase-targeted nucleotide functionalization as a route for enhancing the specificity of small molecule inhibitors. 相似文献
12.
《Bioorganic & medicinal chemistry letters》2014,24(16):3683-3689
Bacterial resistance is inevitable and is a growing concern. It can be addressed only by discovery and development of new agents. However the discovery and development of new antibacterial agents are at an all time low. This article broadly examines the historical as well as current status of antibacterial discovery and provides some perspective as how to address some of the challenges. 相似文献
13.
《Bioorganic & medicinal chemistry》2014,22(17):4566-4571
The National Cancer Institute (NCI) Diversity Set was screened for potential inhibitors of phospho-MurNAc-pentapeptide translocase MraY from Escherichia coli using a primary fluorescence enhancement assay, followed by a secondary radiochemical assay. One new MraY inhibitor was identified from this screen, a naphthylisoquinoline alkaloid michellamine B, which inhibited E. coli MraY (IC50 456 μM) and Bacillus subtilis MraY (IC50 386 μM), and which showed antimicrobial activity against B. subtilis (MIC 16 μg/mL). Following an earlier report of halogenated fluoresceins identified from a combined MraY/MurG screen, three halogenated fluoresceins were tested as inhibitors of E. coli MraY and E. coli MurG, and phloxine B was identified as an inhibitor of E. coli MraY (IC50 32 μM). Molecular docking of inhibitor structures against the structure of Aquifex aeolicus MraY indicates that phloxine B appears to bind to the Mg2+ cofactor in the enzyme active site, while michellamine B binds to a hydrophobic groove formed between transmembrane helices 5 and 9. 相似文献
14.
Dienelactone hydrolase (DLH), an enzyme from the β-ketoadipate pathway, catalyzes the hydrolysis of dienelactone to maleylacetate. Our inhibitor binding studies suggest that its substrate, dienelactone, is held in the active site by hydrophobic interactions around the lactone ring and by the ion pairs between its carboxylate and Arg-81 and Arg-206. Like the cysteine/serine proteases, DLH has a catalytic triad (Cys-123, His-202, Asp-171) and its mechanism probably involves the formation of covalently bound acyl intermediate via a tetrahedral intermediate. Unlike the proteases, DLH seems to protonate the incipient leaving group only after the collapse of the first tetrahedral intermediate, rendering DLH incapable of hydrolyzing amide analogues of its ester substrate. In addition, the triad His probably does not protonate the leaving group (enolate) or deprotonate the water for deacylation; rather, the enolate anion abstracts a proton from water and, in doing so, supplies the hydroxyl for deacylation. © 1993 Wiley-Liss, Inc. 相似文献
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Abstract All ants (Hymenoptera, Formicidae) are highly eusocial insects that are characterized by reproductive division of labor with sterile castes (worker and soldier) helping fertile castes (queen and male) to reproduce.
Ant societies, like other complex animal societies, have developed a sophisticated communication system, in which recognition behaviors are frequently involved Recognition abilities allow individuals to orient and modulate their behaviors effectively and appropriately in response to the characteristics andlor signals expressed by other organisms. Among recognition behaviors, nestmate recognition and kin recognition mechanisms have attracted great attention of sociobiologists, ecologists, insect physiologists and biochemists since 1970's. This is parallel with the popularization of Hamilton's kin selection theory. The present paper aims at reviewing the current understanding on nestmate/kin recognition in ants. This review consists of three parts. The first part concerns the diversity of recognition behaviors and their ecological implications with emphasis on nestmatelkin recognition; in the second part, the current understandings on the mechanism of nestmatelkin recognition are outlined; and in the third part, we discuss the ontogenetic development of nestmate recognition behavior and naturally mixed colonies. The study of the integration mechanism of social parasite may provide heuristic clues to the understanding of kin/nestmate recognition system. 相似文献
Ant societies, like other complex animal societies, have developed a sophisticated communication system, in which recognition behaviors are frequently involved Recognition abilities allow individuals to orient and modulate their behaviors effectively and appropriately in response to the characteristics andlor signals expressed by other organisms. Among recognition behaviors, nestmate recognition and kin recognition mechanisms have attracted great attention of sociobiologists, ecologists, insect physiologists and biochemists since 1970's. This is parallel with the popularization of Hamilton's kin selection theory. The present paper aims at reviewing the current understanding on nestmate/kin recognition in ants. This review consists of three parts. The first part concerns the diversity of recognition behaviors and their ecological implications with emphasis on nestmatelkin recognition; in the second part, the current understandings on the mechanism of nestmatelkin recognition are outlined; and in the third part, we discuss the ontogenetic development of nestmate recognition behavior and naturally mixed colonies. The study of the integration mechanism of social parasite may provide heuristic clues to the understanding of kin/nestmate recognition system. 相似文献
18.
H+/sugar symport in the obligatory aerobic yeastRhodotorula glutinis was analyzed under conditions where the plasma membrane was selectively depolarized by the lipophilic cation tetraphenylphosphonium (TPP+). Control experiments showed that this treatment did not impair the transmembrane pH, the cell energy charge, and the function of plasma membrane H+-ATPase. The kinetic data were fitted to elementary functions derived from a model constructed on the basis of some simplifying premises for ordered (either C + H+ + S or C + S + H+) and random reaction mechanisms. In addition, the comparison of the kinetic parameters in fully energized and depolarized cells provided information about the free carrier charge. It was concluded that the binding sequence of formation of the ternary carrier/H+/substrate complex follows a random mechanism and that the carrier bears a negative charge. 相似文献
19.
本文应用受体阻断、高效液相,6-OHDA 化学损毁神经末梢和放射自显影等多学科技术方法,探讨脊髓苯环立啶受体的心血管效应与去甲肾上腺素能神经系统的关系。结果表明,哌唑嗪、育亨宾均可对抗 ith PCP 的降压和减慢心率作用,ith PCP 产生降压和减慢心率作用时,脊髓脑脊液内 MHPG 的含量升高;用6-OHDA 损毁脊髓 NA 能神经末梢后,ith PCP的降压和减慢心率作用大为减弱,脊髓 PCP 受体密度亦同时大为降低。可以认为,脊髓内有 PCP 受体分布于 NA 能神经末梢上,促进 NA 释放或抑制 NA 重摄取,可能是脊髓 PCP 受体产生心血管抑制效应的重要机理。 相似文献
20.
Forty different chiral molecules were studied by liquid chromatography with a Pirkle-type, (R)-N-(3,5-dinitrobenzoyl) phenylglycine (DNBPG), chiral stationary phase column. The dramatic effect of a small molecular change on chiral recognition was demonstrated using DL-amino acid derivatives. The inductive effect on chiral recognition was also studied using trifluoro-, trichloro-, dichloro-, monochloroacetyl, and acetyl derivatives of four different chiral amines. The study of the enantiomer separation of 11 different crown ethers of 2,2′-binaphthyldiyl showed that the rigidity of the chiral center can be an additional parameter in chiral recognition for the DNBPG phase but not for a β-cyclodextrin bonded chiral phase. It is apparent from this study that steric effects, inductive effects, and molecular rigidity play important roles in chiral recognition with DNBPG chiral stationary phases. 相似文献