A Designed Protein Binding-Pocket to Control Photochemical Isomerization

2018 ◽  
Author(s):  
Bryan J. Lampkin ◽  
Cecilia Monteiro ◽  
Evan T. Powers ◽  
Paige M. Bouc ◽  
Jeffery W. Kelly ◽  
...  
Keyword(s):  
Protein Binding ◽  
Binding Pocket ◽  
Specific Interactions ◽  
Nonspecific Binding ◽  
Design Strategies ◽  
Photochemical Isomerization

<p>ESIPT involves a photochemical isomerization and creates the opportunity for the emission of two distinct wavelengths of light from a single fluorophore. The selectivity between these two wavelengths of emission is dependent on the environment around the fluorophore and suggests the possibility for ratiometric monitoring of protein microenvironments. Unfortunately, nonspecific binding of ESIPT fluorophores does not often lead to dramatic changes in the ratio between the two wavelengths of emission. A protein binding pocket was designed to selectively discriminate between the two channels of emission available to an ESIPT fluorophore. More broadly, this work demonstrates that specific interactions between the protein and the fluorophore are essential to realize strong ratiometric differences between the two possible wavelengths of emission. The design strategies proposed here lead to an ESIPT fluorophore that can discern subtle differences in the interface between two proteins.</p>

A Designed Protein Binding-Pocket to Control Photochemical Isomerization

2018 ◽  
Author(s):  
Bryan J. Lampkin ◽  
Cecilia Monteiro ◽  
Evan T. Powers ◽  
Paige M. Bouc ◽  
Jeffery W. Kelly ◽  
...  
Keyword(s):  
Protein Binding ◽  
Binding Pocket ◽  
Specific Interactions ◽  
Nonspecific Binding ◽  
Design Strategies ◽  
Photochemical Isomerization

<p>ESIPT involves a photochemical isomerization and creates the opportunity for the emission of two distinct wavelengths of light from a single fluorophore. The selectivity between these two wavelengths of emission is dependent on the environment around the fluorophore and suggests the possibility for ratiometric monitoring of protein microenvironments. Unfortunately, nonspecific binding of ESIPT fluorophores does not often lead to dramatic changes in the ratio between the two wavelengths of emission. A protein binding pocket was designed to selectively discriminate between the two channels of emission available to an ESIPT fluorophore. More broadly, this work demonstrates that specific interactions between the protein and the fluorophore are essential to realize strong ratiometric differences between the two possible wavelengths of emission. The design strategies proposed here lead to an ESIPT fluorophore that can discern subtle differences in the interface between two proteins.</p>

scholarly journals A designed protein binding-pocket to control excited-state intramolecular proton transfer fluorescence

2019 ◽  
Vol 17 (5) ◽  
pp. 1076-1080 ◽  
Author(s):  
Bryan J. Lampkin ◽  
Cecilia Monteiro ◽  
Evan T. Powers ◽  
Paige M. Bouc ◽  
Jeffery W. Kelly ◽  
...  
Keyword(s):  
Excited State ◽  
Proton Transfer ◽  
Protein Binding ◽  
Binding Pocket ◽  
Intramolecular Proton Transfer ◽  
Emission Wavelength ◽  
Specific Interactions ◽  
Protein Interfaces

Specific interactions between a protein and fluorophore are essential to realize strong ratiometric differences in emission wavelength at protein–protein interfaces.

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.

scholarly journals De Novo Molecule Design Through Molecular Generative Model Conditioned by 3D Information of Protein Binding Sites

2020 ◽  
Author(s):  
Mingyuan Xu ◽  
Ting Ran ◽  
Hongming Chen
Keyword(s):  
Protein Binding ◽  
De Novo ◽  
Structural Information ◽  
Chemical Space ◽  
Three Dimensional ◽  
Binding Pocket ◽  
Generative Model ◽  
Coarse Grained ◽  
Molecule Design ◽  
3D Information

<p><i>De novo</i> molecule design through molecular generative model is gaining increasing attention in recent years. Here a novel generative model was proposed by integrating the 3D structural information of the protein binding pocket into the conditional RNN (cRNN) model to control the generation of drug-like molecules. In this model, the composition of protein binding pocket is effectively characterized through a coarse-grain strategy and the three-dimensional information of the pocket can be represented by the sorted eigenvalues of the coulomb matrix (EGCM) of the coarse-grained atoms composing the binding pocket. In current work, we used our EGCM method and a previously reported binding pocket descriptor DeeplyTough to train cRNN models and compared their performance. It has been shown that the molecules generated with the control of protein environment information have a clear tendency on generating compounds with higher similarity to the original X-ray bound ligand than normal RNN model and also achieving better performance in terms of docking scores. Our results demonstrate the potential application of EGCM controlled generative model for the targeted molecule generation and guided exploration on the drug-like chemical space. </p><p> </p>

scholarly journals Protein Binding Pocket Optimization for Virtual High-Throughput Screening (vHTS) Drug Discovery

ACS Omega ◽  
2020 ◽  
Vol 5 (24) ◽  
pp. 14297-14307 ◽  
Author(s):  
Dimitris Gazgalis ◽  
Mehreen Zaka ◽  
Bilal Haider Abbasi ◽  
Diomedes E. Logothetis ◽  
Mihaly Mezei ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Protein Binding ◽  
High Throughput ◽  
High Throughput Screening ◽  
Binding Pocket

scholarly journals Surface-based protein binding pocket similarity

2011 ◽  
Vol 79 (9) ◽  
pp. 2746-2763 ◽  
Author(s):  
Russell Spitzer ◽  
Ann E. Cleves ◽  
Ajay N. Jain
Keyword(s):  
Protein Binding ◽  
Binding Pocket

scholarly journals Mechanism of the G-protein mimetic nanobody binding to a muscarinic G-protein-coupled receptor

2018 ◽  
Vol 115 (12) ◽  
pp. 3036-3041 ◽  
Author(s):  
Yinglong Miao ◽  
J. Andrew McCammon
Keyword(s):  
Protein Binding ◽  
G Protein ◽  
Protein Interactions ◽  
Intracellular Signaling ◽  
Md Simulations ◽  
Binding Pocket ◽  
Signaling Proteins ◽  
Protein Protein Interactions ◽  
Intracellular Loops ◽  
G Protein Coupled

Protein–protein binding is key in cellular signaling processes. Molecular dynamics (MD) simulations of protein–protein binding, however, are challenging due to limited timescales. In particular, binding of the medically important G-protein-coupled receptors (GPCRs) with intracellular signaling proteins has not been simulated with MD to date. Here, we report a successful simulation of the binding of a G-protein mimetic nanobody to the M2 muscarinic GPCR using the robust Gaussian accelerated MD (GaMD) method. Through long-timescale GaMD simulations over 4,500 ns, the nanobody was observed to bind the receptor intracellular G-protein-coupling site, with a minimum rmsd of 2.48 Å in the nanobody core domain compared with the X-ray structure. Binding of the nanobody allosterically closed the orthosteric ligand-binding pocket, being consistent with the recent experimental finding. In the absence of nanobody binding, the receptor orthosteric pocket sampled open and fully open conformations. The GaMD simulations revealed two low-energy intermediate states during nanobody binding to the M2 receptor. The flexible receptor intracellular loops contribute remarkable electrostatic, polar, and hydrophobic residue interactions in recognition and binding of the nanobody. These simulations provided important insights into the mechanism of GPCR–nanobody binding and demonstrated the applicability of GaMD in modeling dynamic protein–protein interactions.

scholarly journals Structural insights into human heme oxygenase-1 inhibition by potent and selective azole-based compounds

2013 ◽  
Vol 10 (78) ◽  
pp. 20120697 ◽  
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 ◽  
Potential Interaction ◽  
Structural Basis ◽  
Heme Oxygenase 1 ◽  
Design Strategies ◽  
Inhibitor Binding

The development of heme oxygenase (HO) inhibitors, especially those that are isozyme-selective, promises powerful pharmacological tools to elucidate the regulatory characteristics of the HO system. It is already known that HO has cytoprotective properties and may play a role in several disease states, making it an enticing therapeutic target. Traditionally, the metalloporphyrins have been used as competitive HO inhibitors owing to their structural similarity with the substrate, heme. However, given heme's important role in several other proteins (e.g. cytochromes P450, nitric oxide synthase), non-selectivity is an unfortunate side-effect. Reports that azalanstat and other non-porphyrin molecules inhibited HO led to a multi-faceted effort to develop novel compounds as potent, selective inhibitors of HO. This resulted in the creation of 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, which 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.

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