Overlapping Binding Site for the Endogenous Agonist, Small-Molecule Agonists, and Ago-allosteric Modulators on the Ghrelin Receptor

2008 ◽  
Vol 75 (1) ◽  
pp. 44-59 ◽  
Author(s):  
Birgitte Holst ◽  
Thomas M. Frimurer ◽  
Jacek Mokrosinski ◽  
Tine Halkjaer ◽  
Karina B. Cullberg ◽  
...  
Keyword(s):  
Binding Site ◽  
Small Molecule ◽  
Allosteric Modulators ◽  
Ghrelin Receptor

scholarly journals Discovery of small molecule positive allosteric modulators of the secretin receptor

2021 ◽  
pp. 114451
Author(s):  
Daniela G. Dengler ◽  
Kaleeckal G. Harikumar ◽  
Sirkku Pollari ◽  
Qing Sun ◽  
Brock T. Brown ◽  
...  
Keyword(s):  
Small Molecule ◽  
Allosteric Modulators ◽  
Secretin Receptor ◽  
Positive Allosteric Modulators

scholarly journals Structural Insight into the Two-Step Mechanism of PAI-1 Inhibition by Small Molecule TM5484

2021 ◽  
Vol 22 (3) ◽  
pp. 1482 ◽  
Author(s):  
Machteld Sillen ◽  
Toshio Miyata ◽  
Douglas E. Vaughan ◽  
Sergei V. Strelkov ◽  
Paul J. Declerck
Keyword(s):  
Binding Site ◽  
Small Molecule ◽  
Intracellular Signaling ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Joint Region ◽  
Flexible Joint ◽  
Step Mechanism ◽  
Pai 1

Plasminogen activator inhibitor-1 (PAI-1), a key regulator of the fibrinolytic system, is the main physiological inhibitor of plasminogen activators. By interacting with matrix components, including vitronectin (Vn), PAI-1 plays a regulatory role in tissue remodeling, cell migration, and intracellular signaling. Emerging evidence points to a role for PAI-1 in various pathological conditions, including cardiovascular diseases, cancer, and fibrosis. Targeting PAI-1 is therefore a promising therapeutic strategy in PAI-1-related pathologies. A class of small molecule inhibitors including TM5441 and TM5484, designed to bind the cleft in the central β-sheet A of PAI-1, showed to be potent PAI-1 inhibitors in vivo. However, their binding site has not yet been confirmed. Here, we report two X-ray crystallographic structures of PAI-1 in complex with TM5484. The structures revealed a binding site at the flexible joint region, which is distinct from the presumed binding site. Based on the structural analysis and biochemical data we propose a mechanism for the observed dose-dependent two-step mechanism of PAI-1 inhibition. By binding to the flexible joint region in PAI-1, TM5484 might restrict the structural flexibility of this region, thereby inducing a substrate form of PAI-1 followed by a conversion to an inert form.

scholarly journals Novel dynamic residue network analysis approaches to study homodimeric allosteric modulation in SARS-CoV-2 Mpro and in its evolutionary mutations

2021 ◽  
Author(s):  
Olivier Sheik Amamuddy ◽  
Rita Afriyie Baoteng ◽  
Victor Barozi ◽  
Dorothy Wavinya Nyamai ◽  
Ozlem Tastan Bishop
Keyword(s):  
Binding Site ◽  
Laboratory Strain ◽  
Allosteric Modulators ◽  
Allosteric Communication ◽  
Katz Centrality ◽  
Symmetry Problem ◽  
The Stability ◽  
Allosteric Mechanisms ◽  
Domain I ◽  
Communication Path

The rational search for allosteric modulators and the allosteric mechanisms of these modulators in the presence of evolutionary mutations, including resistant ones, is a relatively unexplored field. Here, we established novel in silico approaches and applied to SARS-CoV-2 main protease (Mpro). First, we identified six potential allosteric modulators (SANC00302, SANC00303, SANC00467, SANC00468, SANC00469, SANC00630) from the South African Natural Compounds Database (SANCDB) bound to the allosteric pocket of Mpro that we determined in our previous work. We also checked the stability of these compounds against Mpro of laboratory strain HCoV-OC43 and identified differences due to residue changes between the two proteins. Next, we focused on understanding the allosteric effects of these modulators on each protomer of the reference Mpro protein, while incorporating the symmetry problem in the functional homodimer. In general, asymmetric behavior of multimeric proteins is not commonly considered in computational analysis. We introduced a novel combinatorial approach and dynamic residue network (DRN) analysis algorithms to examine patterns of change and conservation of critical nodes, according to five independent criteria of network centrality (betweenness centrality (BC), closeness centrality (CC), degree centrality (DC), eigencentrality (EC) and katz centrality (KC)). The relationships and effectiveness of each metric in characterizing allosteric behavior were also investigated. We observed highly conserved network hubs for each averaged DRN metric on the basis of their existence in both protomers in the absence and presence of all ligands, and we called them persistent hubs (residues 17, 111, 112 and 128 for averaged BC; 6, 7, 113, 114, 115, 124, 125, 126, 127 and 128 for averaged CC; 36, 91, 146, 150 and 206 for averaged DC; 7, 115 and 125 for EC; 36, 125 and 146 for KC). We also detected ligand specific signal changes some of which were in or around functional residues (i.e. chameleon switch PHE140). Using EC persistent hubs and ligand introduced hubs we identified a residue communication path between allosteric binding site and catalytic site. Finally, we examined the effects of the mutations on the behavior of the protein in the presence of selected potential allosteric modulators and investigated the ligand stability. The hit compounds showed various levels of stability in the presence of SARS-CoV-2 Mpro mutations, being most stable in A173V, N274D and R279C, and least stable in R60C, N151D V157I, C160S and A255V. SANC00468 was the most stable compound in the 43 mutant protein systems. We further used DRN metric analysis to define cold spots as being those regions that are least impacted, or not impacted, by mutations. One crucial outcome of this study was to show that EC centrality hubs form an allosteric communication path between the allosteric ligand binding site to the active site going through the interface residues of Domain I and II; and this path was either weakened or lost in the presence of some of the mutations. Overall, the results of this study revealed crucial aspects that need to be considered in drug discovery in COVID-19 specifically and in general for rational computational drug design purposes.

Identification of A Novel Small-Molecule Binding Site of the Fat Mass and Obesity Associated Protein (FTO)

2015 ◽  
Vol 58 (18) ◽  
pp. 7341-7348 ◽  
Author(s):  
Wu He ◽  
Bin Zhou ◽  
Weijia Liu ◽  
Meizi Zhang ◽  
Zhenhua Shen ◽  
...  
Keyword(s):  
Binding Site ◽  
Small Molecule ◽  
Fat Mass

scholarly journals Dual Labeling of the CBP/p300 KIX Domain for19F NMR Leads to Identification of a New Small-Molecule Binding Site

ChemBioChem ◽  
2018 ◽  
Vol 19 (9) ◽  
pp. 963-969 ◽  
Author(s):  
Clifford T. Gee ◽  
Keith E. Arntson ◽  
Edward J. Koleski ◽  
Rachel Lynn Staebell ◽  
William C. K. Pomerantz
Keyword(s):  
Binding Site ◽  
Small Molecule ◽  
Kix Domain

scholarly journals Small-Molecule Positive Allosteric Modulators of the β2-Adrenoceptor Isolated from DNA-Encoded Libraries

2018 ◽  
Vol 94 (2) ◽  
pp. 850-861 ◽  
Author(s):  
Seungkirl Ahn ◽  
Biswaranjan Pani ◽  
Alem W. Kahsai ◽  
Eva K. Olsen ◽  
Gitte Husemoen ◽  
...  
Keyword(s):  
Small Molecule ◽  
Allosteric Modulators ◽  
Positive Allosteric Modulators

scholarly journals High resolution structure of human apolipoprotein (a) kringle IV type 2: beyond the lysine binding site

2020 ◽  
Vol 61 (12) ◽  
pp. 1687-1696
Author(s):  
Alice Santonastaso ◽  
Maristella Maggi ◽  
Hugo De Jonge ◽  
Claudia Scotti
Keyword(s):  
High Resolution ◽  
Binding Site ◽  
Small Molecule ◽  
Aminocaproic Acid ◽  
Variable Number ◽  
Crystallographic Structure ◽  
Heparin Binding ◽  
Human Apolipoprotein ◽  
Unique Shape

Lipoprotein (a) [Lp(a)] is characterized by an LDL-like composition in terms of lipids and apoB100, and by one copy of a unique glycoprotein, apo(a). The apo(a) structure is mainly based on the repetition of tandem kringle domains with high homology to plasminogen kringles 4 and 5. Among them, kringle IV type 2 (KIV-2) is present in a highly variable number of genetically encoded repeats, whose length is inversely related to Lp(a) plasma concentration and cardiovascular risk. Despite it being the major component of apo(a), the actual function of KIV-2 is still unclear. Here, we describe the first high-resolution crystallographic structure of this domain. It shows a general fold very similar to other KIV domains with high and intermediate affinity for the lysine analog, ε-aminocaproic acid. Interestingly, KIV-2 presents a lysine binding site (LBS) with a unique shape and charge distribution. KIV-2 affinity for predicted small molecule binders was found to be negligible in surface plasmon resonance experiments; and with the LBS being nonfunctional, we propose to rename it “pseudo-LBS”. Further investigation of the protein by computational small-molecule docking allowed us to identify a possible heparin-binding site away from the LBS, which was confirmed by specific reverse charge mutations abolishing heparin binding. This study opens new possibilities to define the pathogenesis of Lp(a)-related diseases and to facilitate the design of specific therapeutic drugs.

scholarly journals Discovery and Design of Novel Small Molecule GSK-3 Inhibitors Targeting the Substrate Binding Site

2020 ◽  
Vol 21 (22) ◽  
pp. 8709
Author(s):  
Ido Rippin ◽  
Netaly Khazanov ◽  
Shirley Ben Joseph ◽  
Tania Kudinov ◽  
Eva Berent ◽  
...  
Keyword(s):  
Binding Site ◽  
Small Molecule ◽  
Substrate Binding ◽  
Pharmacophore Model ◽  
Drug Induced ◽  
Substrate Binding Site ◽  
Zinc Database ◽  
Competitive Inhibitors ◽  
Ic50 Values ◽  
Critical Binding

The serine/threonine kinase, GSK-3, is a promising drug discovery target for treating multiple pathological disorders. Most GSK-3 inhibitors that were developed function as ATP competitive inhibitors, with typical limitations in specificity, safety and drug-induced resistance. In contrast, substrate competitive inhibitors (SCIs), are considered highly selective, and more suitable for clinical practice. The development of SCIs has been largely neglected in the past because the ambiguous, undefined nature of the substrate-binding site makes them difficult to design. In this study, we used our previously described structural models of GSK-3 bound to SCI peptides, to design a pharmacophore model and to virtually screen the “drug-like” Zinc database (~6.3 million compounds). We identified leading hits that interact with critical binding elements in the GSK-3 substrate binding site and are chemically distinct from known GSK-3 inhibitors. Accordingly, novel GSK-3 SCI compounds were designed and synthesized with IC50 values of~1–4 μM. Biological activity of the SCI compound was confirmed in cells and in primary neurons that showed increased β-catenin levels and reduced tau phosphorylation in response to compound treatment. We have generated a new type of small molecule GSK-3 inhibitors and propose to use this strategy to further develop SCIs for other protein kinases.

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