scholarly journals Plumbagin and oridonin reveal new CRM1 binding sites and NES-binding groove features

2020 ◽  
Author(s):  
Yuqin Lei ◽  
Yuling Li ◽  
Yuping Tan ◽  
Da Jia ◽  
Qingxiang Sun
Keyword(s):  
Binding Sites ◽  
Nuclear Export ◽  
Drug Target ◽  
Structural Basis ◽  
Inhibitor Binding ◽  
Anti Cancer ◽  
Binding Groove ◽  
First Time ◽  
Further Development ◽  
Important Drug

AbstractCRM1 is an important drug target in diseases such as cancer and viral infection. Plumbagin and oridonin, the herbal ingredients with known anti-cancer activities, were reported to inhibit CRM1-mediated nuclear export. However, their modes of CRM1 inhibition are unclear. Here, a multi-mutant of yeast CRM1 was engineered to enable the crystallization of these two small molecules in CRM1’s NES-binding groove. Each structure showed three inhibitor-binding sites, among which two are conserved in humans. Besides the known binding site, another site also participated in oridonin and plumbagin’s CRM1 inhibition. While the plumbagin-bound NES groove resembled the NES-bound groove state, the oridonin-bound groove revealed for the first time a more open NES groove, which may potentially improve cargo-loading through a capture-and-tighten mechanism. Our work thus provides a tool for CRM1 inhibitor crystallization, new insights of CRM1-cargo interaction, and a structural basis for further development of these or other CRM1 inhibitors.

Inhibitor Binding Sites in the Protein Tyrosine Phosphatase SHP-2

2020 ◽  
Vol 20 (11) ◽  
pp. 1017-1030
Author(s):  
Haonan Zhang ◽  
Zhengquan Gao ◽  
Chunxiao Meng ◽  
Xiangqian Li ◽  
Dayong Shi
Keyword(s):  
Small Molecule ◽  
Protein Tyrosine Phosphatase ◽  
Binding Sites ◽  
Drug Target ◽  
Tyrosine Phosphatase ◽  
Cancer Drug ◽  
Cellular Activity ◽  
Binding Modes ◽  
Inhibitor Binding ◽  
Protein Tyrosine

Protein tyrosine phosphatase 2 (SHP-2) has long been proposed as a cancer drug target. Several small-molecule compounds with different mechanisms of SHP-2 inhibition have been reported, but none are commercially available. Pool selectivity over protein tyrosine phosphatase 1 (SHP-1) and a lack of cellular activity have hindered the development of selective SHP-2 inhibitors. In this review, we describe the binding modes of existing inhibitors and SHP-2 binding sites, summarize the characteristics of the sites involved in selectivity, and identify the suitable groups for interaction with the binding sites.

scholarly journals Structural models of full-length JAK2 kinase

2019 ◽  
Author(s):  
Pelin Ayaz ◽  
Henrik M. Hammarén ◽  
Juuli Raivola ◽  
Dina Sharon ◽  
Stevan R. Hubbard ◽  
...  
Keyword(s):  
Drug Target ◽  
Structural Models ◽  
Full Length ◽  
Janus Kinase ◽  
Structural Basis ◽  
Constitutive Activity ◽  
Active Conformation ◽  
Dual Effect ◽  
Dynamics Simulations ◽  
Important Drug

AbstractThe protein JAK2 is a prototypical member of the Janus kinase family, and mediates signals from numerous cytokine receptors. The constitutively active V617F mutant of JAK2 is prevalent in many bone marrow disorders, blood cancers, and autoimmune diseases, and is an important drug target. Structures have been determined for each of the four individual domains making up JAK2, and for certain pairs of these domains, but no structure of full-length JAK2 is available, and thus the mechanisms underlying JAK2 regulation and the aberrant activity of the V617F mutant have been incompletely understood. Here we propose structural models of full-length JAK2 in both its active and inactive forms. Construction of these models was informed by long-timescale molecular dynamics simulations. Subsequent mutagenesis experiments showed that mutations at the putative interdomain interfaces modulated JAK2 activity. The models provide a structural basis for understanding JAK2 autoinhibition and activation, and suggest that the constitutive activity of the V617F mutant may arise from a dual effect of destabilizing the inactive conformation and stabilizing the active conformation.

scholarly journals Structural basis for human TRPC5 channel inhibition by two distinct inhibitors

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Kangcheng Song ◽  
Miao Wei ◽  
Wenjun Guo ◽  
Li Quan ◽  
Yunlu Kang ◽  
...  
Keyword(s):  
Anxiety Disorder ◽  
Binding Sites ◽  
Structural Basis ◽  
Inhibitory Mechanism ◽  
Inhibitor Binding ◽  
Design And Optimization ◽  
Physiological Processes ◽  
Channel Inhibition ◽  
Binding Pockets ◽  
Extracellular Side

TRPC5 channel is a non-selective cation channel that participates diverse physiological processes. TRPC5 inhibitors show promise in the treatment of anxiety disorder, depression and kidney disease. However, the binding sites and inhibitory mechanism of TRPC5 inhibitors remain elusive. Here we present the cryo-EM structures of human TRPC5 in complex with two distinct inhibitors, namely clemizole and HC-070, to the resolution of 2.7 Å. The structures reveal that clemizole binds inside the voltage sensor-like domain of each subunit. In contrast, HC-070 is wedged between adjacent subunits and replaces the glycerol group of a putative DAG molecule near the extracellular side. Moreover, we found mutations in the inhibitor binding pockets altered the potency of inhibitors. These structures suggest that both clemizole and HC-070 exert the inhibitory functions by stabilizing the ion channel in a non-conductive closed state. These results pave the way for further design and optimization of inhibitors targeting human TRPC5.

PLA-based thermogel for the sustained delivery of chemotherapeutics in a mouse model of hepatocellular carcinoma

RSC Advances ◽  
2016 ◽  
Vol 6 (50) ◽  
pp. 44506-44513 ◽  
Author(s):  
Yun-Long Wu ◽  
Han Wang ◽  
Ying-Kun Qiu ◽  
Xian Jun Loh
Keyword(s):  
Hepatocellular Carcinoma ◽  
Mouse Model ◽  
Sustained Delivery ◽  
Anti Cancer ◽  
First Time ◽  
Further Development

This work represents the first time that poly(PEG/PPG/PLA urethane) has been used for the delivery of drugs to tumours in vivo and the encouraging results point to the potential for further development of this thermogel platform for anti-cancer applications.

scholarly journals Search for Structural Basis of Interactions of Biogenic Amines with Human TAAR1 and TAAR6 Receptors

2021 ◽  
Vol 23 (1) ◽  
pp. 209
Author(s):  
Anna V. Glyakina ◽  
Constantine D. Pavlov ◽  
Julia V. Sopova ◽  
Raul R. Gainetdinov ◽  
Elena I. Leonova ◽  
...  
Keyword(s):  
Biogenic Amines ◽  
Binding Sites ◽  
Aminobutyric Acid ◽  
Structural Basis ◽  
Gamma Aminobutyric Acid ◽  
Class A ◽  
Trace Amine ◽  
First Time ◽  
Identification And Characterization

The identification and characterization of ligand-receptor binding sites are important for drug development. Trace amine-associated receptors (TAARs, members of the class A GPCR family) can interact with different biogenic amines and their metabolites, but the structural basis for their recognition by the TAARs is not well understood. In this work, we have revealed for the first time a group of conserved motifs (fingerprints) characterizing TAARs and studied the docking of aromatic (β-phenylethylamine, tyramine) and aliphatic (putrescine and cadaverine) ligands, including gamma-aminobutyric acid, with human TAAR1 and TAAR6 receptors. We have identified orthosteric binding sites for TAAR1 (Asp68, Asp102, Asp284) and TAAR6 (Asp78, Asp112, Asp202). By analyzing the binding results of 7500 structures, we determined that putrescine and cadaverine bind to TAAR1 at one site, Asp68 + Asp102, and to TAAR6 at two sites, Asp78 + Asp112 and Asp112 + Asp202. Tyramine binds to TAAR6 at the same two sites as putrescine and cadaverine and does not bind to TAAR1 at the selected Asp residues. β-Phenylethylamine and gamma-aminobutyric acid do not bind to the TAAR1 and TAAR6 receptors at the selected Asp residues. The search for ligands targeting allosteric and orthosteric sites of TAARs has excellent pharmaceutical potential.

scholarly journals Machine intelligence design of 2019-nCoV drugs

2020 ◽  
Author(s):  
Kaifu Gao ◽  
Duc Duy Nguyen ◽  
Rui Wang ◽  
Guo-Wei Wei
Keyword(s):  
Binding Sites ◽  
Drug Target ◽  
Machine Intelligence ◽  
Respiratory Syndrome Virus ◽  
Viral Protease ◽  
Inhibitor Binding ◽  
Potential Effectiveness ◽  
Sequence Identity ◽  
Hiv Drugs ◽  
Network Complex

AbstractWuhan coronavirus, called 2019-nCoV, is a newly emerged virus that infected more than 9692 people and leads to more than 213 fatalities by January 30, 2020. Currently, there is no effective treatment for this epidemic. However, the viral protease of a coronavirus is well-known to be essential for its replication and thus is an effective drug target. Fortunately, the sequence identity of the 2019-nCoV protease and that of severe-acute respiratory syndrome virus (SARS-CoV) is as high as 96.1%. We show that the protease inhibitor binding sites of 2019-nCoV and SARS-CoV are almost identical, which means all potential anti-SARS-CoV chemotherapies are also potential 2019-nCoV drugs. Here, we report a family of potential 2019-nCoV drugs generated by a machine intelligence-based generative network complex (GNC). The potential effectiveness of treating 2019-nCoV by using some existing HIV drugs is also analyzed.

scholarly journals Structural basis of main proteases of coronavirus bound to drug candidate PF-07321332

2021 ◽  
Author(s):  
Jian Li ◽  
Cheng Lin ◽  
Xuelan Zhou ◽  
Fanglin Zhong ◽  
Pei Zeng ◽  
...  
Keyword(s):  
Binding Site ◽  
Binding Sites ◽  
Binding Mode ◽  
Structural Basis ◽  
Drug Candidate ◽  
Structural Determinants ◽  
Inhibitor Binding ◽  
Mechanism Of Inhibition ◽  
Main Protease ◽  
Multiple Variants

The high mutation rate of COVID-19 and the prevalence of multiple variants strongly support the need for pharmacological options to complement vaccine strategies. One region that appears highly conserved among different genus of coronaviruses is the substrate binding site of the main protease (Mpro or 3CLpro), making it an attractive target for the development of broad-spectrum drugs for multiple coronaviruses. PF-07321332 developed by Pfizer is the first orally administered inhibitor targeting the main protease of SARS-CoV-2, which also has shown potency against other coronaviruses. Here we report three crystal structures of main protease of SARS-CoV-2, SARS-CoV and MERS-CoV bound to the inhibitor PF-07321332. The structures reveal a ligand-binding site that is conserved among SARS-CoV-2, SARS-CoV and MERS-CoV, providing insights into the mechanism of inhibition of viral replication. The long and narrow cavity in the cleft between domains I and II of main protease harbors multiple inhibitor binding sites, where PF-07321332 occupies subsites S1, S2 and S4 and appears more restricted compared with other inhibitors. A detailed analysis of these structures illuminated key structural determinants essential for inhibition and elucidated the binding mode of action of main proteases from different coronaviruses. Given the importance of main protease for the treatment of SARS-CoV-2 infection, insights derived from this study should accelerate the design of safer and more effective antivirals.

Structure ofD-alanine-D-alanine ligase fromYersinia pestis: nucleotide phosphate recognition by the serine loop

2016 ◽  
Vol 72 (1) ◽  
pp. 12-21 ◽  
Author(s):  
Huyen-Thi Tran ◽  
Myoung-Ki Hong ◽  
Ho-Phuong-Thuy Ngo ◽  
Kim-Hung Huynh ◽  
Yeh-Jin Ahn ◽  
...  
Keyword(s):  
Enzyme Kinetics ◽  
Conformational Changes ◽  
Binding Sites ◽  
Drug Target ◽  
Antibacterial Agents ◽  
Binding Mechanism ◽  
Bacterial Peptidoglycan ◽  
Loop 2 ◽  
Hydrolysis Of ◽  
Important Drug

D-Alanyl-D-alanine is an essential precursor of bacterial peptidoglycan and is synthesized by D-alanine-D-alanine ligase (DDL) with hydrolysis of ATP; this reaction makes DDL an important drug target for the development of antibacterial agents. Five crystal structures of DDL fromYersinia pestis(YpDDL) were determined at 1.7–2.5 Å resolution: apo, AMP-bound, ADP-bound, adenosine 5′-(β,γ-imido)triphosphate-bound, and D-alanyl-D-alanine- and ADP-bound structures. YpDDL consists of three domains, in which four loops, loop 1, loop 2 (the serine loop), loop 3 (the ω-loop) and loop 4, constitute the binding sites for two D-alanine molecules and one ATP molecule. Some of them, especially the serine loop and the ω-loop, show flexible conformations, and the serine loop is mainly responsible for the conformational change in substrate nucleotide phosphates. Enzyme-kinetics assays were carried out for both the D-alanine and ATP substrates and a substrate-binding mechanism was proposed for YpDDL involving conformational changes of the loops.

Predicting the Strength of Stacking Interactions Between Heterocycles and Aromatic Amino Acid Side Chains

2019 ◽  
Author(s):  
Andrea N. Bootsma ◽  
Analise C. Doney ◽  
Steven Wheeler
Keyword(s):  
Amino Acid ◽  
Binding Sites ◽  
Aromatic Amino Acid ◽  
Aromatic Amino Acids ◽  
Biologically Active ◽  
Side Chains ◽  
Stacking Interactions ◽  
Inhibitor Binding ◽  
Protein Binding Sites ◽  
Amino Acid Side Chains

<p>Despite the ubiquity of stacking interactions between heterocycles and aromatic amino acids in biological systems, our ability to predict their strength, even qualitatively, is limited. Based on rigorous <i>ab initio</i> data, we have devised a simple predictive model of the strength of stacking interactions between heterocycles commonly found in biologically active molecules and the amino acid side chains Phe, Tyr, and Trp. This model provides rapid predictions of the stacking ability of a given heterocycle based on readily-computed heterocycle descriptors. We show that the values of these descriptors, and therefore the strength of stacking interactions with aromatic amino acid side chains, follow simple predictable trends and can be modulated by changing the number and distribution of heteroatoms within the heterocycle. This provides a simple conceptual model for understanding stacking interactions in protein binding sites and optimizing inhibitor binding in drug design.</p>

Structural Insights into Azole-based Inhibitors of Heme Oxygenase-1: Development of Selective Compounds for Therapeutic Applications

2019 ◽  
Vol 25 (42) ◽  
pp. 5803-5821 ◽  
Author(s):  
Mona N. Rahman ◽  
Dragic Vukomanovic ◽  
Jason Z. Vlahakis ◽  
Walter A. Szarek ◽  
Kanji Nakatsu ◽  
...  
Keyword(s):  
Heme Oxygenase ◽  
Competitive Inhibition ◽  
Cytochromes P450 ◽  
Structural Similarity ◽  
Binding Pocket ◽  
Initial Study ◽  
Structural Basis ◽  
Heme Oxygenase 1 ◽  
Design Strategies ◽  
Inhibitor Binding

The development of isozyme-selective heme oxygenase (HO) inhibitors promises powerful pharmacological tools to elucidate the regulatory characteristics of the HO system. It is already known that HO has cytoprotective properties with a role in several disease states; thus, it is an enticing therapeutic target. Historically, the metalloporphyrins have been used as competitive HO inhibitors based on their structural similarity to the substrate, heme. However, heme’s important role in several other proteins (e.g. cytochromes P450, nitric oxide synthase), results in non-selectivity being an unfortunate side effect. Reports that azalanstat and other non-porphyrin molecules inhibited HO led to a multi-faceted effort over a decade ago to develop novel compounds as potent, selective inhibitors of HO. The result was the creation of the first generation of non-porphyrin based, non-competitive inhibitors with selectivity for HO, including a subset with isozyme selectivity for HO-1. Using X-ray crystallography, the structures of several complexes of HO-1 with novel inhibitors have been elucidated and provided insightful information regarding the salient features required for inhibitor binding. This included the structural basis for non-competitive inhibition, flexibility and adaptability of the inhibitor binding pocket, and multiple, potential interaction subsites, all of which can be exploited in future drug-design strategies. Notably, HO-1 inhibitors are of particular interest for the treatment of hyperbilirubinemia and certain types of cancer. Key features based on this initial study have already been used by others to discover additional potential HO-1 inhibitors. Moreover, studies have begun to use selected compounds and determine their effects in some disease models.

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