Browsing by Subject "Structure-Activity Relationship"
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Item Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes-7(MDPI, 2020-06-28) Gutschow, Michael; Eynde, Jean Jacques Vanden; Jampilek, Josef; Kang, CongBao; Mangoni, Arduino A.; Fossa, Paola; Karaman, Rafik; Trabocchi, Andrea; Scott, Peter J. H.; Reynisson, Johannes; Rapposelli, Simona; Galdiero, Stefania; Winum, Jean-Yves; Brullo, Chiara; Prokai-Tatrai, Katalin; Sharma, Arun K.; Schapira, Matthieu; Azuma, Yasu-Taka; Cerchia, Laura; Spetea, Mariana; Torri, Giangiacomo; Collina, Simona; Geronikaki, Athina; Garcia-Sosa, Alfonso T.; Vasconcelos, M. Helena; Sousa, Maria Emilia; Kosalec, Ivan; Tuccinardi, Tiziano; Duarte, Iola F.; Salvador, Jorge A. R.; Bertinaria, Massimo; Pellecchia, Maurizio; Amato, Jussara; Rastelli, Giulio; Gomes, Paula A. C.; Guedes, Rita C.; Sabatier, Jean-Marc; Estevez-Braun, Ana; Pagano, Bruno; Mangani, Stefano; Ragno, Rino; Kokotos, George; Brindisi, Margherita; Gonzalez, Florenci V.; Borges, Fernanda; Miloso, Mariarosaria; Rautio, Jarkko; Munoz-Torrero, DiegoBreakthroughs in Medicinal Chemistry [...].Item Design and Synthesis of Conformationally Flexible Scaffold as Bitopic Ligands for Potent D(3)-Selective Antagonists(MDPI, 2023-01-09) Kim, Ho Young; Lee, Ji Youn; Hsieh, Chia-Ju; Taylor, Michelle; Luedtke, Robert R.; Mach, Robert H.Previous studies have confirmed that the binding of D(3) receptor antagonists is competitively inhibited by endogenous dopamine despite excellent binding affinity for D(3) receptors. This result urges the development of an alternative scaffold that is capable of competing with dopamine for binding to the D(3) receptor. Herein, an SAR study was conducted on metoclopramide that incorporated a flexible scaffold for interaction with the secondary binding site of the D(3) receptor. The alteration of benzamide substituents and secondary binding fragments with aryl carboxamides resulted in excellent D(3) receptor affinities (Ki = 0.8-13.2 nM) with subtype selectivity to the D(2) receptor ranging from 22- to 180-fold. The beta-arrestin recruitment assay revealed that 21c with 4-(pyridine-4-yl)benzamide can compete well against dopamine with the highest potency (IC(50) = 1.3 nM). Computational studies demonstrated that the high potency of 21c and its analogs was the result of interactions with the secondary binding site of the D(3) receptor. These compounds also displayed minimal effects for other GPCRs except moderate affinity for 5-HT(3) receptors and TSPO. The results of this study revealed that a new class of selective D(3) receptor antagonists should be useful in behavioral pharmacology studies and as lead compounds for PET radiotracer development.Item Structure and Dynamics of Cas9 HNH Domain Catalytic State(Springer Nature, 2017-12-08) Zuo, Zhicheng; Liu, JinThe bacterial CRISPR-Cas9 immune system has been harnessed as a powerful and versatile genome-editing tool and holds immense promise for future therapeutic applications. Despite recent advances in understanding Cas9 structures and its functional mechanism, little is known about the catalytic state of the Cas9 HNH nuclease domain, and identifying how the divalent metal ions affect the HNH domain conformational transition remains elusive. A deeper understanding of Cas9 activation and its cleavage mechanism can enable further optimization of Cas9-based genome-editing specificity and efficiency. Using two distinct molecular dynamics simulation techniques, we have obtained a cross-validated catalytically active state of Cas9 HNH domain primed for cutting the target DNA strand. Moreover, herein we demonstrate the essential roles of the catalytic Mg(2+) for the active state formation and stability. Importantly, we suggest that the derived catalytic conformation of the HNH domain can be exploited for rational engineering of Cas9 variants with enhanced specificity.