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 Virtual Screening of FDA Approved Drugs Against Nsp15 Endoribonuclease from SARS CoV-2

2020 ◽  
Author(s):  
Althaf Shaik ◽  
Nalini Natarajan ◽  
Sivapriya Kirubakaran ◽  
Vijay Thiruvenkatam
Keyword(s):  
Crystal Structure ◽  
Molecular Dynamics ◽  
Virtual Screening ◽  
Computational Approach ◽  
Important Target ◽  
Structure Solution ◽  
Wet Lab ◽  
Approved Drugs ◽  
Dynamics Simulations ◽  
Fda Approved Drugs

<p>This manuscript shows a detailed computational approach of carefully curated drugs that can potentially act against Nsp15, an endoribonuclease necessary for SARS-CoV2 multiplication. In our work, we have considered maximum resources available on Nsp15 including the recent crystal structure solution of the protein. Owing to the increase in demand for a cure for COVID-19, we have attempted to virtually screen an important target of SARS-CoV2 using the pre-existing FDA approved drugs. The main advantage of our work is our multi-step approach in validating our hits. We have performed initial High Throughput Virtual Screening (HTVS) of 2910 drugs. The top 20 hits were subjected to rigorous molecular docking and molecular dynamics simulations yielding a final number of 5 potential hits. In this global emergency, we have made a humble yet critical attempt by undertaking this work; we hope that our work once published may be of help in carrying out appropriate wet-lab work. </p><p></p>We declare that this manuscript is original, has not been published before and is not currently being considered for publication elsewhere."

scholarly journals Virtual Screening of FDA Approved Drugs Against Nsp15 Endoribonuclease from SARS CoV-2

2020 ◽  
Author(s):  
Althaf Shaik ◽  
Nalini Natarajan ◽  
Sivapriya Kirubakaran ◽  
Vijay Thiruvenkatam
Keyword(s):  
Crystal Structure ◽  
Molecular Dynamics ◽  
Virtual Screening ◽  
Computational Approach ◽  
Important Target ◽  
Structure Solution ◽  
Wet Lab ◽  
Approved Drugs ◽  
Dynamics Simulations ◽  
Fda Approved Drugs

<p>This manuscript shows a detailed computational approach of carefully curated drugs that can potentially act against Nsp15, an endoribonuclease necessary for SARS-CoV2 multiplication. In our work, we have considered maximum resources available on Nsp15 including the recent crystal structure solution of the protein. Owing to the increase in demand for a cure for COVID-19, we have attempted to virtually screen an important target of SARS-CoV2 using the pre-existing FDA approved drugs. The main advantage of our work is our multi-step approach in validating our hits. We have performed initial High Throughput Virtual Screening (HTVS) of 2910 drugs. The top 20 hits were subjected to rigorous molecular docking and molecular dynamics simulations yielding a final number of 5 potential hits. In this global emergency, we have made a humble yet critical attempt by undertaking this work; we hope that our work once published may be of help in carrying out appropriate wet-lab work. </p><p></p>We declare that this manuscript is original, has not been published before and is not currently being considered for publication elsewhere."

scholarly journals Ligand Docking Methods to Recognize Allosteric Inhibitors for G-protein Coupled Receptors

2020 ◽  
Author(s):  
K Harini ◽  
S Jayashree ◽  
Vikas Tiwari ◽  
Sneha Vishwanath ◽  
Ramanathan Sowdhamini
Keyword(s):  
Binding Site ◽  
G Protein ◽  
Drug Targets ◽  
G Protein Coupled Receptors ◽  
Ligand Docking ◽  
Computational Docking ◽  
Cellular Processes ◽  
Activation Mechanisms ◽  
Approved Drugs ◽  
G Protein Coupled

G-protein coupled receptors (GPCRs) are large protein families known to be important in many cellular processes. They are well known for their allosteric activation mechanisms. They are drug targets for several FDA-approved drugs. We have investigated the diversity of the ligand binding site for these class of proteins against their cognate ligands using computational docking, even if their structures are known in the ligand-complexed form. The cognate ligand of some of these receptors dock at allosteric binding site, with better score than the binding at the conservative site. Further, ligands obtained from GLASS database, which consists of experimentally verified GPCR ligands, also show allosteric binding to GPCRs. The allosteric binders show strong affinity to the binding site, though the residues at the binding site are not conserved across GPCR subfamilies.

scholarly journals Molecular mechanism of biased signaling in a prototypical G protein–coupled receptor

Science ◽  
2020 ◽  
Vol 367 (6480) ◽  
pp. 881-887 ◽  
Author(s):  
Carl-Mikael Suomivuori ◽  
Naomi R. Latorraca ◽  
Laura M. Wingler ◽  
Stephan Eismann ◽  
Matthew C. King ◽  
...  
Keyword(s):  
G Protein ◽  
Protein A ◽  
Binding Pocket ◽  
Great Promise ◽  
G Protein Coupled Receptor ◽  
Structural Mechanism ◽  
Biased Signaling ◽  
Dynamics Simulations ◽  
Effective Drugs ◽  
G Protein Coupled

Biased signaling, in which different ligands that bind to the same G protein–coupled receptor preferentially trigger distinct signaling pathways, holds great promise for the design of safer and more effective drugs. Its structural mechanism remains unclear, however, hampering efforts to design drugs with desired signaling profiles. Here, we use extensive atomic-level molecular dynamics simulations to determine how arrestin bias and G protein bias arise at the angiotensin II type 1 receptor. The receptor adopts two major signaling conformations, one of which couples almost exclusively to arrestin, whereas the other also couples effectively to a G protein. A long-range allosteric network allows ligands in the extracellular binding pocket to favor either of the two intracellular conformations. Guided by this computationally determined mechanism, we designed ligands with desired signaling profiles.

scholarly journals Three Different Mutations in the DNA Topoisomerase 1B in Leishmania Infantum Contribute to Resistance to Antitumor Drug Topotecan

2021 ◽  
Author(s):  
Chloe Rosa-Teijeiro ◽  
Victoria Wagner ◽  
Audrey Corbeil ◽  
Ilda d'Annessa ◽  
Philippe Leprohon ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Large Subunit ◽  
Binding Pocket ◽  
Next Generation Sequencing Data ◽  
Whole Genome ◽  
Sequencing Data ◽  
Theoretical Approaches ◽  
In The Wild ◽  
Approved Drugs ◽  
Dynamics Simulations

Abstract BackgroundThe evolution of drug resistance is one of the biggest challenges in leishmaniasis and has prompted the need for new antileishmanial drugs. Repurposing of approved drugs is a faster and very attractive strategy that is gaining supporters worldwide. Different anticancer topoisomerase 1B (TOP1B) inhibitors have shown strong antileishmanial activity and promising selective indices, supporting the potential repurposing of these drugs. However, cancer cells and Leishmania share the ability to become rapidly resistant. The aim of this study was to complete a whole-genome exploration of the effects caused by exposure to topotecan in order to highlight the potential mechanisms deployed by Leishmania to favor its survival in the presence of a TOP1B inhibitor. MethodsWe used a combination of stepwise drug-resistance selection, whole-genome sequencing, functional validation, and theoretical approaches to explore the propensity of and potential mechanisms deployed by three independent clones of L. infantum to resist the action of TOP1B-inhibitor topotecan. ResultsWe demonstrated that L. infantum is capable of becoming resistant to high concentrations of topotecan without impaired growth ability. No gene deletions or amplifications were identified from the next-generation sequencing data in any of the three resistant lines, ruling out the overexpression of efflux pumps as the preferred mechanism of topotecan resistance. We identified three different mutations in the large subunit of the leishmanial TOP1B (Top1BF187Y, Top1BG191A and Top1BW232R). Overexpression of these mutated alleles in the wild-type background led to high levels of resistance to topotecan. Computational molecular dynamics simulations, in both covalent and non-covalent complexes, showed that these mutations have an effect on the arrangement of the catalytic pentad and on the interaction of these residues with surrounding amino acids and DNA. This altered architecture of the binding pocket results in decreased persistence of topotecan in the ternary complex. ConclusionsThis work helps elucidate the previously-unclear potential mechanisms of topotecan resistance in Leishmania by mutations in the large subunit of TOP1B and provides a valuable clue for the design of improved inhibitors to combat resistance in both leishmaniasis and cancer. Our data highlights the importance of including drug-resistance evaluation in drug-discovery cascades.

scholarly journals Computational Identification of a Putative Allosteric Binding Pocket in TMPRSS2

2021 ◽  
Vol 8 ◽  
Author(s):  
Jacopo Sgrignani ◽  
Andrea Cavalli
Keyword(s):  
Binding Pocket ◽  
Activation Process ◽  
Computational Docking ◽  
Allosteric Inhibitor ◽  
Pocket Computer ◽  
Inactive Form ◽  
Covalent Adduct ◽  
Dynamics Simulations ◽  
Transmembrane Serine Protease ◽  
Allosteric Binding Pocket

Camostat, nafamostat, and bromhexine are inhibitors of the transmembrane serine protease TMPRSS2. The inhibition of TMPRSS2 has been shown to prevent the viral infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other viruses. However, while camostat and nafamostat inhibit TMPRSS2 by forming a covalent adduct, the mode of action of bromhexine remains unclear. TMPRSS2 is autocatalytically activated from its inactive form, zymogen, through a proteolytic cleavage that promotes the binding of Ile256 to a putative allosteric pocket (A-pocket). Computer simulations, reported here, indicate that Ile256 binding induces a conformational change in the catalytic site, thus providing the atomistic rationale to the activation process of the enzyme. Furthermore, computational docking and molecular dynamics simulations indicate that bromhexine competes with the N-terminal Ile256 for the same binding site, making it a potential allosteric inhibitor. Taken together, these findings provide the atomistic basis for the development of more selective and potent TMPRSS2 inhibitors.

scholarly journals Potential COVID-19 papain-like protease PLpro inhibitors: repurposing FDA-approved drugs

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9965 ◽  
Author(s):  
Valentina L. Kouznetsova ◽  
Aidan Zhang ◽  
Mahidhar Tatineni ◽  
Mark A. Miller ◽  
Igor F. Tsigelny
Keyword(s):  
Crystal Structure ◽  
Pharmacophore Model ◽  
Binding Pocket ◽  
Free Energies ◽  
Inhibitor Binding ◽  
Drug List ◽  
Approved Drugs ◽  
Docking Interaction ◽  
Potential Inhibitors ◽  
Fda Approved Drugs

Using the crystal structure of SARS-CoV-2 papain-like protease (PLpro) as a template, we developed a pharmacophore model of functional centers of the PLpro inhibitor-binding pocket. With this model, we conducted data mining of the conformational database of FDA-approved drugs. This search identified 147 compounds that can be potential inhibitors of SARS-CoV-2 PLpro. The conformations of these compounds underwent 3D fingerprint similarity clusterization, followed by docking of possible conformers to the binding pocket of PLpro. Docking of random compounds to the binding pocket of protease was also done for comparison. Free energies of the docking interaction for the selected compounds were lower than for random compounds. The drug list obtained includes inhibitors of HIV, hepatitis C, and cytomegalovirus (CMV), as well as a set of drugs that have demonstrated some activity in MERS, SARS-CoV, and SARS-CoV-2 therapy. We recommend testing of the selected compounds for treatment of COVID-19

scholarly journals Ligand Docking Methods to Recognize Allosteric Inhibitors for G-protein Coupled Receptors

2021 ◽  
Author(s):  
Harini K ◽  
Jayashree S ◽  
Vikas Tiwari ◽  
Sneha Vishwanath ◽  
Ramanathan Sowdhamini
Keyword(s):  
Binding Site ◽  
G Protein ◽  
Drug Targets ◽  
Computational Approach ◽  
G Protein Coupled Receptors ◽  
Ligand Docking ◽  
Allosteric Site ◽  
Computational Docking ◽  
Approved Drugs ◽  
G Protein Coupled

Abstract BackgroundG-protein coupled receptors (GPCRs) are large protein families known to be important in many cellular processes. They are well known for their allosteric activation mechanisms. They are drug targets for several FDA-approved drugs. We have investigated the diversity of the ligand binding site for these class of proteins against their cognate ligands using computational docking, even if their structures are known in the ligand-complexed form. ResultsThe cognate ligand of some of these receptors dock at allosteric binding site, with better score than the binding at the conservative site. Further, ligands obtained from GLASS database, which consists of experimentally verified GPCR ligands, also show allosteric binding to GPCRs. The allosteric binders show strong affinity to the binding site, though the residues at the binding site are not conserved across GPCR subfamilies.ConclusionsBased on our computational approach it was found that the residues at the allosteric site are not as conserved as in the cognate binding site, which might explain the specificity of a particular GPCR. Further, for certain GPCRs, some of their known cognate ligands were predicted to have better binding preference towards the allosteric site than orthosteric site and therefore this computational approach can assist in the prediction of allosteric binders for GPCRs.

scholarly journals The structures of E. coli NfsA bound to the antibiotic nitrofurantoin; to 1,4- benzoquinone and to FMN.

2021 ◽  
Author(s):  
Martin Alan Day ◽  
David Jarrom ◽  
Andrew J Christofferson ◽  
Antonio E Graziano ◽  
Ross Anderson ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Crystal Structures ◽  
Furan Ring ◽  
Hydride Transfer ◽  
Binding Pocket ◽  
Phosphate Binding ◽  
Free Protein ◽  
E Coli ◽  
Nitrofuran Antibiotics ◽  
Dynamics Simulations

NfsA is a dimeric flavoprotein that catalyses the reduction of nitroaromatics and quinones by NADPH. This reduction is required for the activity of nitrofuran antibiotics. The crystal structure of free E. coli NfsA and several homologues have been determined previously, but there is no structure of the enzyme with ligands. We present here crystal structures of oxidised E. coli NfsA in the presence of several ligands, including the antibiotic nitrofurantoin. Nitrofurantoin binds with the furan ring, rather than the nitro group that is reduced, near the N5 of the FMN. Molecular dynamics simulations show that this orientation is only favourable in the oxidised enzyme, while potentiometry suggests that little semiquinone is formed in the free protein. This suggests that the reduction occurs by direct hydride transfer from FMNH- to nitrofurantoin bound in the reverse orientation to that in the crystal structure. We present a model of nitrofurantoin bound to reduced NfsA in a viable hydride transfer orientation. The substrate 1,4-benzoquinone and the product hydroquinone are positioned close to the FMN N5 in the respective crystal structures with NfsA, suitable for reaction, but are mobile within the active site. The structure with a second FMN, bound as a ligand, shows that a mobile loop in the free protein forms a phosphate-binding pocket. NfsA is specific for NADPH and a similar conformational change, forming a phosphate-binding pocket, is likely to also occur with the natural cofactor.

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