scholarly journals On the role of water density fluctuations in the inhibition of a proton channel

2016 ◽  
Vol 113 (52) ◽  
pp. E8359-E8368 ◽  
Author(s):  
Eleonora Gianti ◽  
Lucie Delemotte ◽  
Michael L. Klein ◽  
Vincenzo Carnevale
Keyword(s):  
Water Distribution ◽  
Binding Free Energy ◽  
Salt Bridge ◽  
Binding Pocket ◽  
Density Fluctuations ◽  
Proton Channel ◽  
General Strategy ◽  
Water Density ◽  
Pore Waters ◽  
Computational Docking

Hv1 is a transmembrane four-helix bundle that transports protons in a voltage-controlled manner. Its crucial role in many pathological conditions, including cancer and ischemic brain damage, makes Hv1 a promising drug target. Starting from the recently solved crystal structure of Hv1, we used structural modeling and molecular dynamics simulations to characterize the channel’s most relevant conformations along the activation cycle. We then performed computational docking of known Hv1 inhibitors, 2-guanidinobenzimidazole (2GBI) and analogs. Although salt-bridge patterns and electrostatic potential profiles are well-defined and distinctive features of activated versus nonactivated states, the water distribution along the channel lumen is dynamic and reflects a conformational heterogeneity inherent to each state. In fact, pore waters assemble into intermittent hydrogen-bonded clusters that are replaced by the inhibitor moieties upon ligand binding. The entropic gain resulting from releasing these conformationally restrained waters to the bulk solvent is likely a major contributor to the binding free energy. Accordingly, we mapped the water density fluctuations inside the pore of the channel and identified the regions of maximum fluctuation within putative binding sites. Two sites appear as outstanding: One is the already known binding pocket of 2GBI, which is accessible to ligands from the intracellular side; the other is a site located at the exit of the proton permeation pathway. Our analysis of the waters confined in the hydrophobic cavities of Hv1 suggests a general strategy for drug discovery that can be applied to any ion channel.

scholarly journals Nature Potential for COVID-19: Targeting SARS-CoV-2 Mpro Inhibitor with Bioactive Compound

2021 ◽  
Author(s):  
Kaushik Kumar Bharadwaj ◽  
Tanmay Sarkar ◽  
Arabinda Ghosh ◽  
Debabrat Baishya ◽  
Bijuli Rabha ◽  
...  
Keyword(s):  
Binding Energy ◽  
Antiviral Activity ◽  
Binding Free Energy ◽  
Bioactive Compound ◽  
Binding Pocket ◽  
Stable Conformation ◽  
Lipinski’S Rule ◽  
Macrolactin A

<p>Corona viruses were first identified in 1931 and SARS-CoV-2 is the most recent. COVID-19 is a pandemic that put most of the world on lockdown and the search for therapeutic drugs is still on-going. Therefore, this study uses <i>in silico</i> screening to identify natural bioactive compounds from fruits, herbaceous plants and marine invertebrates that are able to inhibit protease activity in SARS-CoV-2(PDB: 6LU7). We have used various screening strategies such as drug likeliness, antiviral activity value prediction, molecular docking, ADME (absorption, distribution, metabolism, and excretion), molecular dynamics (MD) simulation and MM/GBSA (molecular mechanics/generalized born and surface area continuum solvation). 17 compounds were shortlisted using Lipinski’s rule. 5 compounds revealed significantly good predicted antiviral activity values and out of them only 2 compounds, Macrolactin A and Stachyflin, showed good binding energy values of -9.22 and -8.00 kcal/mol within the binding pocket, catalytic residues (HIS 41 and CYS 145) of M<sup>pro</sup>. These two compounds were further analyzed for their ADME properties. The ADME evaluation of these 2 compounds suggested that they could be effective as therapeutic agents for developing drugs for clinical trials. MD simulations showed that protein-ligand complexes of Macrolactin A and Stachyflin were stable for 100 nano seconds. The MM/GBSA calculations of M<sup>pro</sup> – Macrolactin A complex indicated higher binding free energy (-42.58 ± 6.35 kcal/mol) with M<sup>pro </sup>protein target receptor (6LU7). DCCM and PCA analysis on the residual movement in the MD trajectories confirmed the good stability on Macrolactin A bound state of 6LU7. This signify the stable conformation of 6LU7 with high binding energy with Macrolactin A. Thus, this study showed that Macrolactin A could be an effective therapeutical agent for SARS-CoV-2protease (6LU7) inhibition. Additional <i>in vitro </i>and<i> in vivo </i>validations are needed to determine efficacy and dose of Macrolactin A in biological systems.</p>

scholarly journals Crystal structure of the human NK1 tachykinin receptor

2018 ◽  
Vol 115 (52) ◽  
pp. 13264-13269 ◽  
Author(s):  
Jie Yin ◽  
Karen Chapman ◽  
Lindsay D. Clark ◽  
Zhenhua Shao ◽  
Dominika Borek ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Substance P ◽  
Binding Pocket ◽  
Computational Docking ◽  
Tachykinin Receptor ◽  
Approved Drugs ◽  
Dynamics Simulations ◽  
Receptor Modulators ◽  
Further Development ◽  
G Protein Coupled

The NK1 tachykinin G-protein–coupled receptor (GPCR) binds substance P, the first neuropeptide to be discovered in mammals. Through activation of NK1R, substance P modulates a wide variety of physiological and disease processes including nociception, inflammation, and depression. Human NK1R (hNK1R) modulators have shown promise in clinical trials for migraine, depression, and emesis. However, the only currently approved drugs targeting hNK1R are inhibitors for chemotherapy-induced nausea and vomiting (CINV). To better understand the molecular basis of ligand recognition and selectivity, we solved the crystal structure of hNK1R bound to the inhibitor L760735, a close analog of the drug aprepitant. Our crystal structure reveals the basis for antagonist interaction in the deep and narrow orthosteric pocket of the receptor. We used our structure as a template for computational docking and molecular-dynamics simulations to dissect the energetic importance of binding pocket interactions and model the binding of aprepitant. The structure of hNK1R is a valuable tool in the further development of tachykinin receptor modulators for multiple clinical applications.

scholarly journals Characterization of Glyceollins as Novel Aryl Hydrocarbon Receptor Ligands and Their Role in Cell Migration

2020 ◽  
Vol 21 (4) ◽  
pp. 1368 ◽  
Author(s):  
Thu Ha Pham ◽  
Sylvain Lecomte ◽  
Remy Le Guevel ◽  
Aurélie Lardenois ◽  
Bertrand Evrard ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Aryl Hydrocarbon Receptor ◽  
Synergistic Effects ◽  
Binding Pocket ◽  
Migration And Invasion ◽  
Therapeutic Effects ◽  
Computational Docking ◽  
Aryl Hydrocarbon ◽  
Glyceollin I

Recent studies strongly support the use of the aryl hydrocarbon receptor (AhR) as a therapeutic target in breast cancer. Glyceollins, a group of soybean phytoalexins, are known to exert therapeutic effects in chronic human diseases and also in cancer. To investigate the interaction between glyceollin I (GI), glyceollin II (GII) and AhR, a computational docking analysis, luciferase assays, immunofluorescence and transcriptome analyses were performed with different cancer cell lines. The docking experiments predicted that GI and GII can enter into the AhR binding pocket, but their interactions with the amino acids of the binding site differ, in part, from those interacting with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Both GI and GII were able to weakly and partially activate AhR, with GII being more potent. The results from the transcriptome assays showed that approximately 10% of the genes regulated by TCDD were also modified by both GI and GII, which could have either antagonistic or synergistic effects upon TCDD activation. In addition, we report here, on the basis of phenotype, that GI and GII inhibit the migration of triple-negative (ER-, PgR-, HER2NEU-) MDA-MB-231 breast cancer cells, and that they inhibit the expression of genes which code for important regulators of cell migration and invasion in cancer tissues. In conclusion, GI and GII are AhR ligands that should be further investigated to determine their usefulness in cancer treatments.

scholarly journals Pathways to dewetting in hydrophobic confinement

2015 ◽  
Vol 112 (27) ◽  
pp. 8181-8186 ◽  
Author(s):  
Richard C. Remsing ◽  
Erte Xi ◽  
Srivathsan Vembanur ◽  
Sumit Sharma ◽  
Pablo G. Debenedetti ◽  
...  
Keyword(s):  
Density Fluctuations ◽  
Sampling Techniques ◽  
Water Density ◽  
Hydrophobic Surfaces ◽  
Macroscopic Theory ◽  
Advanced Sampling ◽  
Gaussian Statistics ◽  
Kinetics Of ◽  
Peculiar Nature ◽  
Kinetic Barriers

Liquid water can become metastable with respect to its vapor in hydrophobic confinement. The resulting dewetting transitions are often impeded by large kinetic barriers. According to macroscopic theory, such barriers arise from the free energy required to nucleate a critical vapor tube that spans the region between two hydrophobic surfaces—tubes with smaller radii collapse, whereas larger ones grow to dry the entire confined region. Using extensive molecular simulations of water between two nanoscopic hydrophobic surfaces, in conjunction with advanced sampling techniques, here we show that for intersurface separations that thermodynamically favor dewetting, the barrier to dewetting does not correspond to the formation of a (classical) critical vapor tube. Instead, it corresponds to an abrupt transition from an isolated cavity adjacent to one of the confining surfaces to a gap-spanning vapor tube that is already larger than the critical vapor tube anticipated by macroscopic theory. Correspondingly, the barrier to dewetting is also smaller than the classical expectation. We show that the peculiar nature of water density fluctuations adjacent to extended hydrophobic surfaces—namely, the enhanced likelihood of observing low-density fluctuations relative to Gaussian statistics—facilitates this nonclassical behavior. By stabilizing isolated cavities relative to vapor tubes, enhanced water density fluctuations thus stabilize novel pathways, which circumvent the classical barriers and offer diminished resistance to dewetting. Our results thus suggest a key role for fluctuations in speeding up the kinetics of numerous phenomena ranging from Cassie–Wenzel transitions on superhydrophobic surfaces, to hydrophobically driven biomolecular folding and assembly.

scholarly journals Identification of potential inhibitors for Bruton’s Tyrosine Kinase (BTK) based on pharmacophore-based virtual screening

2020 ◽  
Vol 10 (3) ◽  
pp. 5472-5477
Keyword(s):  
Tyrosine Kinase ◽  
Binding Free Energy ◽  
Pharmacophore Model ◽  
Binding Pocket ◽  
Dynamics Simulation ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Immunological Disorders ◽  
B Lineage ◽  
Differentiation And Proliferation

Bruton’s tyrosine kinase (BTK) is well known for its role in the development, differentiation and proliferation of B-lineage cells. The dysregulation of BTK is closely related with the immunological disorders and BTK targeting is commonly studied in the treatment of immunological disorders. Here pharmacophore model was developed, and screening against ZINC database retrieved 1337 hit molecules of potential BTK inhibitors. Molecular docking was performed for all molecules and analysis on the top docked molecules revealed that the ligands interacted well in the binding pocket of BTK. A 100-ns molecular dynamics simulation confirmed the docked pose of ligand, while the calculation of binding free energy indicated that the hit molecule has comparable affinity with native ligand of BTK (2V3).

scholarly journals A novel Hv1 inhibitor reveals a new mechanism of inhibition of a voltage-sensing domain

2021 ◽  
Vol 153 (9) ◽  
Author(s):  
Chang Zhao ◽  
Liang Hong ◽  
Saleh Riahi ◽  
Victoria T. Lim ◽  
Douglas J. Tobias ◽  
...  
Keyword(s):  
Md Simulations ◽  
Binding Pocket ◽  
Proton Channel ◽  
Voltage Sensing ◽  
Voltage Gated ◽  
Functional Studies ◽  
Mechanism Of Inhibition ◽  
Target Binding ◽  
Voltage Gated Ion Channels ◽  
Pore Domain

Voltage-gated sodium, potassium, and calcium channels consist of four voltage-sensing domains (VSDs) that surround a central pore domain and transition from a down state to an up state in response to membrane depolarization. While many types of drugs bind pore domains, the number of organic molecules known to bind VSDs is limited. The Hv1 voltage-gated proton channel is made of two VSDs and does not contain a pore domain, providing a simplified model for studying how small ligands interact with VSDs. Here, we describe a ligand, named HIF, that interacts with the Hv1 VSD in the up and down states. We find that HIF rapidly inhibits proton conduction in the up state by blocking the open channel, as previously described for 2-guanidinobenzimidazole and its derivatives. HIF, however, interacts with a site slowly accessible in the down state. Functional studies and MD simulations suggest that this interaction traps the compound in a narrow pocket lined with charged residues within the VSD intracellular vestibule, which results in slow recovery from inhibition. Our findings point to a “wrench in gears” mechanism whereby side chains within the binding pocket trap the compound as the teeth of interlocking gears. We propose that the use of screening strategies designed to target binding sites with slow accessibility, similar to the one identified here, could lead to the discovery of new ligands capable of interacting with VSDs of other voltage-gated ion channels in the down state.

scholarly journals Molecular Dynamics Simulation Framework to Probe the Binding Hypothesis of CYP3A4 Inhibitors

2019 ◽  
Vol 20 (18) ◽  
pp. 4468 ◽  
Author(s):  
Kiani ◽  
Ranaghan ◽  
Jabeen ◽  
Mulholland
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Binding Free Energy ◽  
Binding Pocket ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Metabolic Enzyme ◽  
New Chemical Entities ◽  
Cyp3a4 Inhibitors ◽  
Cytochrome P450 Family

The Cytochrome P450 family of heme-containing proteins plays a major role in catalyzing phase I metabolic reactions, and the CYP3A4 subtype is responsible for the metabolism of many currently marketed drugs. Additionally, CYP3A4 has an inherent affinity for a broad spectrum of structurally diverse chemical entities, often leading to drug–drug interactions mediated by the inhibition or induction of the metabolic enzyme. The current study explores the binding of selected highly efficient CYP3A4 inhibitors by docking and molecular dynamics (MD) simulation protocols and their binding free energy calculated using the WaterSwap method. The results indicate the importance of binding pocket residues including Phe57, Arg105, Arg106, Ser119, Arg212, Phe213, Thr309, Ser312, Ala370, Arg372, Glu374, Gly481 and Leu483 for interaction with CYP3A4 inhibitors. The residue-wise decomposition of the binding free energy from the WaterSwap method revealed the importance of binding site residues Arg106 and Arg372 in the stabilization of all the selected CYP3A4-inhibitor complexes. The WaterSwap binding energies were further complemented with the MM(GB/PB)SA results and it was observed that the binding energies calculated by both methods do not differ significantly. Overall, our results could guide towards the use of multiple computational approaches to achieve a better understanding of CYP3A4 inhibition, subsequently leading to the design of highly specific and efficient new chemical entities with suitable ADMETox properties and reduced side effects.

Molecular cloning, sequence characteristics, and tissue expression analysis of glucagon receptor gene in Bama minipig

2020 ◽  
Vol 100 (3) ◽  
pp. 536-546
Author(s):  
Cuiping An ◽  
Kaiyi Zhang ◽  
Wenjuan Zhu ◽  
Yanzhen Bi ◽  
Tianwen Wu ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Receptor Gene ◽  
Three Dimensional ◽  
Salt Bridge ◽  
Binding Pocket ◽  
Tissue Expression ◽  
Dimensional Structure ◽  
Glucagon Receptor ◽  
Tissue Expression Analysis ◽  
Glucose And Lipid Metabolism

Recent studies have shown that the glucagon receptor (GCGR) plays an important role in the development of type 2 diabetes mellitus. Both pigs and humans exhibit significantly similar behaviors in their glucose and lipid metabolism. In this study, the obtained Bama minipig GCGR coding sequence was 1437 bp encoding 479 amino acids (AA), which demonstrated higher sequence homology with humans than other species. It showed the highest expression profile in the liver, followed by the lung and kidney. In addition, the three-dimensional structure analysis showed that the porcine GCGR protein also had a classic sevenfold transmembrane region and a stalk region at the N-terminus for ligand binding. The stalk region of GCGR possessed five AA variations. The ligand binding pocket of GCGR has one AA variation in the key region, none of which affected the glucagon binding verified by the crystal structure mutagenesis in humans. There was no variation found in the region of membrane anchoring, hydrophobic bond, salt bridge, and hydrogen bond. However, the Gly40Ser mutation in mice resulted in major diseases, meaning that pigs are more suitable for the evaluation of GCGR-related drugs than mice.

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