scholarly journals How does a small molecule bind at a cryptic binding site?

2021 ◽  
Author(s):  
Yibing Shan ◽  
Venkatesh P. Mysore ◽  
Abba E. Leffler ◽  
Eric T. Kim ◽  
Shiori Sagawa ◽  
...  
Keyword(s):  
Small Molecules ◽  
Binding Site ◽  
Small Molecule ◽  
Protein Interactions ◽  
Binding Sites ◽  
Rational Design ◽  
Structural Information ◽  
Interleukin 2 ◽  
Md Simulations ◽  
Drug Binding

Protein-protein interactions (PPIs) are ubiquitous biomolecular processes that are central to virtually all aspects of cellular function. Identifying small molecules that modulate specific disease-related PPIs is a strategy with enormous promise for drug discovery. The design of drugs to disrupt PPIs is challenging, however, because many potential drug-binding sites at PPI interfaces are "cryptic": When unoccupied by a ligand, cryptic sites are often flat and featureless, and thus not readily recognizable in crystal structures, with the geometric and chemical characteristics of typical small-molecule binding sites only emerging upon ligand binding. The rational design of small molecules to inhibit specific PPIs would benefit from a better understanding of how such molecules bind at PPI interfaces. To this end, we have conducted unbiased, all-atom MD simulations of the binding of four small-molecule inhibitors (SP4206 and three SP4206 analogs) to interleukin 2 (IL2)—which performs its function by forming a PPI with its receptor—without incorporating any prior structural information about the ligands' binding. In multiple binding events, a small molecule settled into a stable binding pose at the PPI interface of IL2, resulting in a protein–small-molecule binding site and pose virtually identical to that observed in an existing crystal structure of the IL2-SP4206 complex. Binding of the small molecule stabilized the IL2 binding groove, which when the small molecule was not bound emerged only transiently and incompletely. Moreover, free energy perturbation (FEP) calculations successfully distinguished between the native and non-native IL2–small-molecule binding poses found in the simulations, suggesting that binding simulations in combination with FEP may provide an effective tool for identifying cryptic binding sites and determining the binding poses of small molecules designed to disrupt PPI interfaces by binding to such sites.

scholarly journals Molecular basis of small-molecule binding to α-synuclein

2021 ◽  
Author(s):  
Paul Robustelli ◽  
Alain Ibanez-de-Opakua ◽  
Cecily Campbell-Bezat ◽  
Fabrizio Giordanetto ◽  
Stefan Becker ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Rational Design ◽  
Intrinsically Disordered Proteins ◽  
Md Simulations ◽  
Structural Features ◽  
Atomic Level ◽  
Disordered Proteins ◽  
Structure Based Drug Design ◽  
Intrinsically Disordered

AbstractIntrinsically disordered proteins (IDPs) are implicated in many human diseases. They have generally not been amenable to conventional structure-based drug design, however, because their intrinsic conformational variability has precluded an atomic-level understanding of their binding to small molecules. Here we present long-timescale, atomic-level molecular dynamics (MD) simulations of monomeric α-synuclein (an IDP whose aggregation is associated with Parkinson’s disease) binding the small-molecule drug fasudil in which the observed protein-ligand interactions were found to be in good agreement with previously reported NMR chemical shift data. In our simulations, fasudil, when bound, favored certain charge-charge and π-stacking interactions near the C terminus of α-synuclein, but tended not to form these interactions simultaneously, rather breaking one of these interactions and forming another nearby (a mechanism we term dynamic shuttling). Further simulations with small molecules chosen to modify these interactions yielded binding affinities and key structural features of binding consistent with subsequent NMR experiments, suggesting the potential for MD-based strategies to facilitate the rational design of small molecules that bind with disordered proteins.

A Structural Perspective on the Modulation of Protein-Protein Interactions with Small Molecules

2018 ◽  
Vol 18 (8) ◽  
pp. 700-713 ◽  
Author(s):  
Habibe Cansu Demirel ◽  
Tunca Dogan ◽  
Nurcan Tuncbag
Keyword(s):  
Small Molecules ◽  
Protein Interactions ◽  
Hot Spots ◽  
Rational Design ◽  
Structural Information ◽  
Enzymatic Reactions ◽  
Protein Protein Interactions ◽  
Cellular Processes ◽  
Cellular Pathways ◽  
Structural Methods

Protein-Protein Interactions (PPIs) are the key components in many cellular processes including signaling pathways, enzymatic reactions and epigenetic regulation. Abnormal interactions of some proteins may be pathogenic and cause various disorders including cancer and neurodegenerative diseases. Although inhibiting PPIs with small molecules is a challenging task, it gained an increasing interest because of its strong potential for drug discovery and design. The knowledge of the interface as well as the structural and chemical characteristics of the PPIs and their roles in the cellular pathways is necessary for a rational design of small molecules to modulate PPIs. In this study, we review the recent progress in the field and detail the physicochemical properties of PPIs including binding hot spots with a focus on structural methods. Then, we review recent approaches for structural prediction of PPIs. Finally, we revisit the concept of targeting PPIs from a systems biology perspective and we refer to approaches that are usually employed when the structural information is not present.

scholarly journals A journey in bioinspired supramolecular chemistry: from molecular tweezers to small molecules that target myotonic dystrophy

2016 ◽  
Vol 12 ◽  
pp. 125-138 ◽  
Author(s):  
Steven C Zimmerman
Keyword(s):  
Small Molecules ◽  
Supramolecular Chemistry ◽  
Myotonic Dystrophy ◽  
Small Molecule ◽  
Early Life ◽  
Rational Design ◽  
Early Experience ◽  
Therapeutic Agents ◽  
Early Career ◽  
Molecular Tweezers

This review summarizes part of the author’s research in the area of supramolecular chemistry, beginning with his early life influences and early career efforts in molecular recognition, especially molecular tweezers. Although designed to complex DNA, these hosts proved more applicable to the field of host–guest chemistry. This early experience and interest in intercalation ultimately led to the current efforts to develop small molecule therapeutic agents for myotonic dystrophy using a rational design approach that heavily relies on principles of supramolecular chemistry. How this work was influenced by that of others in the field and the evolution of each area of research is highlighted with selected examples.

scholarly journals Nanomechanics combined with HDX reveal allosteric drug binding sites of CFTR NBD1

2021 ◽  
Author(s):  
Rita Padanyi ◽  
Bianka Farkas ◽  
Hedvig Tordai ◽  
Balint Kiss ◽  
Helmut Grubmuller ◽  
...  
Keyword(s):  
Binding Sites ◽  
Thermal Stabilization ◽  
Drug Efficacy ◽  
Md Simulations ◽  
Drug Binding ◽  
Structural Defects ◽  
Mechanical Resistance ◽  
Atomic Force ◽  
Δf508 Cftr ◽  
Hydrogen Deuterium

Cystic fibrosis is most frequently caused by the deletion of F508 (ΔF508) in CFTR's nucleotide binding domain 1 (NBD1), thereby compromising CFTR folding, stability and domain assembly. Limitation to develop a successful therapy has been attributed to the lack of molecules that synergistically facilitate folding by targeting distinct structural defects of ΔF508-CFTR. To improve drug efficacy by targeting the ΔF508-NBD1 folding and stability, and to study potential ΔF508-NBD1 allosteric corrector binding sites at the atomic level, we combined molecular dynamics (MD) simulations, atomic force spectroscopy (AFM) and hydrogen-deuterium exchange (HDX) experiments to elucidate the mechanical and thermal stabilization mechanisms of ΔF508-NBD1 by 5-bromoindole-3-acetic acid (BIA). MD and AFM allowed us to describe unfolding intermediates and forces acting during NBD1 mechanical unfolding. Application of the low-potency corrector BIA increased the mechanical resistance of the ΔF508-NBD1 α-subdomain, which was confirmed as a binding site by computational modeling and HDX experiments. Our results underline the complementarity of MD and AFM despite their different pulling speeds and provide a possible strategy to improve folding correctors.

Rational Design of Selective Small-Molecule Inhibitors for β-Catenin/B-Cell Lymphoma 9 Protein–Protein Interactions

2015 ◽  
Vol 137 (38) ◽  
pp. 12249-12260 ◽  
Author(s):  
Logan R. Hoggard ◽  
Yongqiang Zhang ◽  
Min Zhang ◽  
Vanja Panic ◽  
John A. Wisniewski ◽  
...  
Keyword(s):  
B Cell ◽  
Small Molecule ◽  
Protein Interactions ◽  
Rational Design ◽  
Small Molecule Inhibitors ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Protein Protein Interactions ◽  
Catenin B

scholarly journals A network of phosphatidylinositol 4,5-bisphosphate binding sites regulates gating of the Ca2+-activated Cl− channel ANO1 (TMEM16A)

2019 ◽  
Vol 116 (40) ◽  
pp. 19952-19962 ◽  
Author(s):  
Kuai Yu ◽  
Tao Jiang ◽  
YuanYuan Cui ◽  
Emad Tajkhorshid ◽  
H. Criss Hartzell
Keyword(s):  
Protein Interactions ◽  
Binding Sites ◽  
Neuronal Excitability ◽  
Computational Study ◽  
Channel Gating ◽  
Md Simulations ◽  
Fluid Secretion ◽  
Hydroxyl Groups ◽  
Binding Modes ◽  
Cytoplasmic Extension

ANO1 (TMEM16A) is a Ca2+-activated Cl− channel that regulates diverse cellular functions including fluid secretion, neuronal excitability, and smooth muscle contraction. ANO1 is activated by elevation of cytosolic Ca2+ and modulated by phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. Here, we describe a closely concerted experimental and computational study, including electrophysiology, mutagenesis, functional assays, and extended sampling of lipid–protein interactions with molecular dynamics (MD) to characterize PI(4,5)P2 binding modes and sites on ANO1. ANO1 currents in excised inside-out patches activated by 270 nM Ca2+ at +100 mV are increased by exogenous PI(4,5)P2 with an EC50 = 1.24 µM. The effect of PI(4,5)P2 is dependent on membrane voltage and Ca2+ and is explained by a stabilization of the ANO1 Ca2+-bound open state. Unbiased atomistic MD simulations with 1.4 mol% PI(4,5)P2 in a phosphatidylcholine bilayer identified 8 binding sites with significant probability of binding PI(4,5)P2. Three of these sites captured 85% of all ANO1–PI(4,5)P2 interactions. Mutagenesis of basic amino acids near the membrane–cytosol interface found 3 regions of ANO1 critical for PI(4,5)P2 regulation that correspond to the same 3 sites identified by MD. PI(4,5)P2 is stabilized by hydrogen bonding between amino acid side chains and phosphate/hydroxyl groups on PI(4,5)P2. Binding of PI(4,5)P2 alters the position of the cytoplasmic extension of TM6, which plays a crucial role in ANO1 channel gating, and increases the accessibility of the inner vestibule to Cl− ions. We propose a model consisting of a network of 3 PI(4,5)P2 binding sites at the cytoplasmic face of the membrane allosterically regulating ANO1 channel gating.

scholarly journals Structure-based prediction of ligand–protein interactions on a genome-wide scale

2017 ◽  
Vol 114 (52) ◽  
pp. 13685-13690 ◽  
Author(s):  
Howook Hwang ◽  
Fabian Dey ◽  
Donald Petrey ◽  
Barry Honig
Keyword(s):  
Binding Site ◽  
Protein Interactions ◽  
Kinase Inhibitors ◽  
Structural Information ◽  
Structural Alignment ◽  
Scoring Function ◽  
A Genome ◽  
Small Molecule Ligands ◽  
Wide Scale ◽  
Approved Drugs

We report a template-based method, LT-scanner, which scans the human proteome using protein structural alignment to identify proteins that are likely to bind ligands that are present in experimentally determined complexes. A scoring function that rapidly accounts for binding site similarities between the template and the proteins being scanned is a crucial feature of the method. The overall approach is first tested based on its ability to predict the residues on the surface of a protein that are likely to bind small-molecule ligands. The algorithm that we present, LBias, is shown to compare very favorably to existing algorithms for binding site residue prediction. LT-scanner’s performance is evaluated based on its ability to identify known targets of Food and Drug Administration (FDA)-approved drugs and it too proves to be highly effective. The specificity of the scoring function that we use is demonstrated by the ability of LT-scanner to identify the known targets of FDA-approved kinase inhibitors based on templates involving other kinases. Combining sequence with structural information further improves LT-scanner performance. The approach we describe is extendable to the more general problem of identifying binding partners of known ligands even if they do not appear in a structurally determined complex, although this will require the integration of methods that combine protein structure and chemical compound databases.

NMR for the design of functional mimetics of protein-protein interactions: one key is in the building of bridges

1998 ◽  
Vol 76 (2-3) ◽  
pp. 177-188 ◽  
Author(s):  
Jianxing Song ◽  
Feng Ni
Keyword(s):  
Protein Interactions ◽  
Binding Sites ◽  
Experimental Approach ◽  
Structural Information ◽  
Peptide Ligands ◽  
Protein Protein Interactions ◽  
Binding Residues ◽  
Related Proteins ◽  
Binding Inhibitors

Using the design of bivalent and bridge-binding inhibitors of thrombin as an example, we review an NMR-based experimental approach for the design of functional mimetics of protein-protein interactions. The strategy includes: (i) identification of binding residues in peptide ligands by differential resonance perturbation, (ii) determination of protein-bound structures of peptide ligands by use of transferred NOEs, (iii) minimization of larger protein and peptide ligands on the basis of NMR structural information, and (iv) linkage of two weakly binding mimetics to produce an inhibitor with enhanced affinity and specificity. This approach can be especially effective for the design of potent and selective functional mimetics of protein-protein interactions because it is less likely that the surfaces of two related proteins or enzymes share two identical binding sites or regions.Key words: NMR, protein-protein interactions, functional mimetics, bridge-binding inhibitors, thrombin.

scholarly journals Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
James O’Connell ◽  
John Porter ◽  
Boris Kroeplien ◽  
Tim Norman ◽  
Stephen Rapecki ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Protein Interactions ◽  
General Mechanism ◽  
Protein Protein Interactions ◽  
Biologic Drugs ◽  
Small Molecule Drugs ◽  
Necrosis Factor

AbstractTumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn’s disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for a class of small molecule drugs capable of modulating TNF function by stabilising a naturally sampled, receptor-incompetent conformation of TNF. Furthermore, this approach may prove to be a more general mechanism for inhibiting protein–protein interactions.

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