Genetic evidence for the existence of two quinone related inhibitor binding sites in NADH-CoQ reductase

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 ab initio 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.

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Inhibitor Binding Sites in the Protein Tyrosine Phosphatase SHP-2

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557520666200303130833 ◽

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.

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Diffusion-enhanced energy transfer shows accessibility of ribonucleic acid polymerase inhibitor binding sites

Biochemistry ◽

10.1021/bi00506a025 ◽

1981 ◽

Vol 20 (3) ◽

pp. 610-617 ◽

Cited By ~ 25

Author(s):

Claude F. Meares ◽

Lyle S. Rice

Keyword(s):

Energy Transfer ◽

Ribonucleic Acid ◽

Binding Sites ◽

Inhibitor Binding ◽

Polymerase Inhibitor

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Location of Inhibitor Binding Sites in the Human Inducible Prostaglandin E Synthase, MPGES1

Biochemistry ◽

10.1021/bi2010448 ◽

2011 ◽

Vol 50 (35) ◽

pp. 7684-7693 ◽

Cited By ~ 26

Author(s):

Edward B. Prage ◽

Sven-Christian Pawelzik ◽

Laura S. Busenlehner ◽

Kwangho Kim ◽

Ralf Morgenstern ◽

...

Keyword(s):

Binding Sites ◽

Prostaglandin E ◽

Inhibitor Binding ◽

Prostaglandin E Synthase

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Structural basis for human TRPC5 channel inhibition by two distinct inhibitors

eLife ◽

10.7554/elife.63429 ◽

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.

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

10.26434/chemrxiv.7628939.v3 ◽

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

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 ab initio 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.

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Molecular Basis for Resistance of Acanthamoeba Tubulins to All Major Classes of Antitubulin Compounds

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00355-07 ◽

2007 ◽

Vol 52 (3) ◽

pp. 1133-1135 ◽

Cited By ~ 22

Author(s):

Fiona L. Henriquez ◽

Paul R. Ingram ◽

Stephen P. Muench ◽

David W. Rice ◽

Craig W. Roberts

Keyword(s):

Amino Acid ◽

Binding Sites ◽

Molecular Basis ◽

Eukaryotic Cells ◽

Inhibitor Binding ◽

Critical Amino Acid

ABSTRACT Tubulin is essential to eukaryotic cells and is targeted by several antineoplastics, herbicides, and antimicrobials. We demonstrate that Acanthamoeba spp. are resistant to five antimicrotubule compounds, unlike any other eukaryote studied so far. Resistance correlates with critical amino acid differences within the inhibitor binding sites of the tubulin heterodimers.

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