Identification of Phosphoinositide-3 Kinases Delta and Gamma Dual Inhibitors Based on the p110δ/γ Crystal Structure

Background: Phosphoinositide-3 kinases (PI3Ks) are key signaling molecules that affect a diverse array of biological processes in cells, including proliferation, differentiation, survival, and metabolism. The abnormal activity of PI3K signals is closely related to the occurrence of many diseases, which has become a very promising drug target, especially for the treatment of cancer. PI3Kδ/γ inhibitors can reduce toxicity concerns for chronic indications such as asthma and rheumatoid arthritis compared with pan PI3Ks inhibitors. Methods: With the aim of finding more effective PI3Kδ/γ dual inhibitors, virtual screening, ADMET prediction Molecular Dynamics (MD) simulations and MM-GBSA were executed based on the known p110δ/γ crystal structure. Compound ZINC28564067 with high docking score and low toxicity was obtained. Results: By MD simulations and MM-GBSA, we could observe that ZINC28564067 had more favorable conformation binding to the PI3Kδ/γ than the original ligands. Conclusion: The results provided a rapid approach for the discovery of novel PI3Kδ/γ dual inhibitors which might be a potential anti-tumor lead compound.

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Can molecular dynamics simulations improve the structural accuracy and virtual screening performance of GPCR models?

PLoS Computational Biology ◽

10.1371/journal.pcbi.1008936 ◽

2021 ◽

Vol 17 (5) ◽

pp. e1008936

Author(s):

Jon Kapla ◽

Ismael Rodriguez Espigares ◽

Flavio Ballante ◽

Jana Selent ◽

Jens Carlsson

Keyword(s):

Crystal Structure ◽

Molecular Dynamics ◽

Virtual Screening ◽

Ligand Binding ◽

Md Simulations ◽

Binding Mode ◽

Extracellular Loop ◽

Loop Region ◽

Screening Performance ◽

Virtual Screening Performance

The determination of G protein-coupled receptor (GPCR) structures at atomic resolution has improved understanding of cellular signaling and will accelerate the development of new drug candidates. However, experimental structures still remain unavailable for a majority of the GPCR family. GPCR structures and their interactions with ligands can also be modelled computationally, but such predictions have limited accuracy. In this work, we explored if molecular dynamics (MD) simulations could be used to refine the accuracy of in silico models of receptor-ligand complexes that were submitted to a community-wide assessment of GPCR structure prediction (GPCR Dock). Two simulation protocols were used to refine 30 models of the D3 dopamine receptor (D3R) in complex with an antagonist. Close to 60 μs of simulation time was generated and the resulting MD refined models were compared to a D3R crystal structure. In the MD simulations, the transmembrane helix region of the models generally drifted further away from the crystal structure conformation. However, MD refinement was able to improve the accuracy of the ligand binding mode and the second extracellular loop region. The best refinement protocol improved agreement with the experimentally observed ligand binding mode for a majority of the models. Receptor structures with improved virtual screening performance, which was assessed by molecular docking of ligands and decoys, could also be identified among the MD refined models. Application of weak restraints to the transmembrane helixes in the MD simulations further improved predictions of the ligand binding mode and second extracellular loop. These results provide guidelines for application of MD refinement in prediction of GPCR-ligand complexes and directions for further method development.

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Molecular Dynamics Simulation of Homo-DNA: The Role of Crystal Packing in Duplex Conformation

Crystals ◽

10.3390/cryst9100532 ◽

2019 ◽

Vol 9 (10) ◽

pp. 532

Author(s):

Jonathan H. Sheehan ◽

Jarrod A. Smith ◽

Pradeep S. Pallan ◽

Terry P. Lybrand ◽

Martin Egli

Keyword(s):

Crystal Structure ◽

Molecular Dynamics ◽

Nucleic Acid ◽

Base Pair ◽

Crystal Packing ◽

Md Simulations ◽

Conformational Flexibility ◽

Dynamics Simulation ◽

Dna Duplex ◽

Solution Studies

The (4′→6′)-linked DNA homolog 2′,3′-dideoxy-β-D-glucopyranosyl nucleic acid (dideoxy-glucose nucleic acid or homo-DNA) exhibits stable self-pairing of the Watson–Crick and reverse-Hoogsteen types, but does not cross-pair with DNA. Molecular modeling and NMR solution studies of homo-DNA duplexes pointed to a conformation that was nearly devoid of a twist and a stacking distance in excess of 4.5 Å. By contrast, the crystal structure of the homo-DNA octamer dd(CGAATTCG) revealed a right-handed duplex with average values for helical twist and rise of ca. 15° and 3.8 Å, respectively. Other key features of the structure were strongly inclined base-pair and backbone axes in the duplex with concomitant base-pair slide and cross-strand stacking, and the formation of a dimer across a crystallographic dyad with inter-duplex base swapping. To investigate the conformational flexibility of the homo-DNA duplex and a potential influence of lattice interactions on its geometry, we used molecular dynamics (MD) simulations of the crystallographically observed dimer of duplexes and an isolated duplex in the solution state. The dimer of duplexes showed limited conformational flexibility, and key parameters such as helical rise, twist, and base-pair slide exhibited only minor fluctuations. The single duplex was clearly more flexible by comparison and underwent partial unwinding, albeit without significant lengthening. Thus, base stacking was preserved in the isolated duplex and two adenosines extruded from the stack in the dimer of duplexes were reinserted into the duplex and pair with Ts in a Hoogsteen mode. Our results confirmed that efficient stacking in homo-DNA seen in the crystal structure of a dimer of duplexes was maintained in the separate duplex. Therefore, lattice interactions did not account for the different geometries of the homo-DNA duplex in the crystal and earlier models that resembled inclined ladders with large base-pair separations that precluded efficient stacking.

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Molecular docking, pharmacophore based virtual screening and molecular dynamics studies towards the identification of potential leads for the management of H. pylori

RSC Advances ◽

10.1039/c9ra03281a ◽

2019 ◽

Vol 9 (45) ◽

pp. 26176-26208 ◽

Cited By ~ 2

Author(s):

Manoj G. Damale ◽

Rajesh B. Patil ◽

Siddique Akber Ansari ◽

Hamad M. Alkahtani ◽

Abdulrahman A. Almehizia ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Virtual Screening ◽

Md Simulations ◽

Pharmacophore Modeling ◽

Gastric Ulcers ◽

Computational Approaches ◽

Gastric Cancers ◽

H Pylori

Computational approaches such as pharmacophore modeling, virtual screening and MD simulations were explored to find the potential hits as H. pylori specific panC inhibitors for the management of gastric ulcers and gastric cancers.

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Molecular dynamics simulations of the Cx26 hemichannel: Evaluation of structural models with Brownian dynamics

The Journal of General Physiology ◽

10.1085/jgp.201110679 ◽

2011 ◽

Vol 138 (5) ◽

pp. 475-493 ◽

Cited By ~ 62

Author(s):

Taekyung Kwon ◽

Andrew L. Harris ◽

Angelo Rossi ◽

Thaddeus A. Bargiello

Keyword(s):

Crystal Structure ◽

Molecular Dynamics ◽

Posttranslational Modifications ◽

Brownian Dynamics ◽

Ion Selectivity ◽

Physiological Role ◽

Md Simulations ◽

Cation Selectivity ◽

Gap Junction Channel ◽

Channel Properties

The recently published crystal structure of the Cx26 gap junction channel provides a unique opportunity for elucidation of the structure of the conductive connexin pore and the molecular determinants of its ion permeation properties (conductance, current–voltage [I-V] relations, and charge selectivity). However, the crystal structure was incomplete, most notably lacking the coordinates of the N-terminal methionine residue, which resides within the pore, and also lacking two cytosolic domains. To allow computational studies for comparison with the known channel properties, we completed the structure. Grand canonical Monte Carlo Brownian dynamics (GCMC/BD) simulations of the completed and the published Cx26 hemichannel crystal structure indicate that the pore is too narrow to permit significant ion flux. The GCMC/BD simulations predict marked inward current rectification and almost perfect anion selectivity, both inconsistent with known channel properties. The completed structure was refined by all-atom molecular dynamics (MD) simulations (220 ns total) in an explicit solvent and POPC membrane system. These MD simulations produced an equilibrated structure with a larger minimal pore diameter, which decreased the height of the permeation barrier formed by the N terminus. GCMC/BD simulations of the MD-equilibrated structure yielded more appropriate single-channel conductance and less anion/cation selectivity. However, the simulations much more closely matched experimentally determined I-V relations when the charge effects of specific co- and posttranslational modifications of Cx26 previously identified by mass spectrometry were incorporated. We conclude that the average equilibrated structure obtained after MD simulations more closely represents the open Cx26 hemichannel structure than does the crystal structure, and that co- and posttranslational modifications of Cx26 hemichannels are likely to play an important physiological role by defining the conductance and ion selectivity of Cx26 channels. Furthermore, the simulations and data suggest that experimentally observed heterogeneity in Cx26 I-V relations can be accounted for by variation in co- and posttranslational modifications.

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In SilicoIdentification of Potent PPAR-γAgonists from Traditional Chinese Medicine: A Bioactivity Prediction, Virtual Screening, and Molecular Dynamics Study

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2014/192452 ◽

2014 ◽

Vol 2014 ◽

pp. 1-19 ◽

Cited By ~ 6

Author(s):

Kuan-Chung Chen ◽

Calvin Yu-Chian Chen

Keyword(s):

Molecular Dynamics ◽

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Virtual Screening ◽

Prediction Models ◽

Protein Complexes ◽

Md Simulations ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptors ◽

Key Residues

The peroxisome proliferator-activated receptors (PPARs) related to regulation of lipid metabolism, inflammation, cell proliferation, differentiation, and glucose homeostasis by controlling the related ligand-dependent transcription of networks of genes. They are used to be served as therapeutic targets against metabolic disorder, such as obesity, dyslipidemia, and diabetes; especially, PPAR-γis the most extensively investigated isoform for the treatment of dyslipidemic type 2 diabetes. In this study, we filter compounds of traditional Chinese medicine (TCM) using bioactivities predicted by three distinct prediction models before the virtual screening. For the top candidates, the molecular dynamics (MD) simulations were also utilized to investigate the stability of interactions between ligand and PPAR-γprotein. The top two TCM candidates, 5-hydroxy-L-tryptophan and abrine, have an indole ring and carboxyl group to form the H-bonds with the key residues of PPAR-γprotein, such as residues Ser289 and Lys367. The secondary amine group of abrine also stabilized an H-bond with residue Ser289. From the figures of root mean square fluctuations (RMSFs), the key residues were stabilized in protein complexes with 5-Hydroxy-L-tryptophan and abrine as control. Hence, we propose 5-hydroxy-L-tryptophan and abrine as potential lead compounds for further study in drug development process with the PPAR-γprotein.

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Biomolecular Solvation Structure Revealed by Molecular Dynamics Simulations

10.26434/chemrxiv.7492676.v1 ◽

2018 ◽

Author(s):

Michael Wall ◽

Gaetano Calabró ◽

Christopher I. Bayly ◽

David Mobley ◽

Gregory Warren

Keyword(s):

Crystal Structure ◽

Molecular Dynamics ◽

Neutron Diffraction ◽

Water Structure ◽

Md Simulations ◽

Neutron Density ◽

Macromolecular Crystallography ◽

Field Development ◽

Biomolecular Solvation ◽

Dynamics Simulations

In order to compare ordered water positions from experiment with those from molecular dynamics (MD) simulations, a number of MD models of water structure in crystalline endoglucanase were calculated. The starting MD model was derived from a joint X-ray and neutron diffraction crystal structure, enabling the use of experimentally assigned protonation states. Simulations were performed in the crystalline state, using a periodic 2x2x2 supercell with explicit solvent. Water electron and neutron density maps were computed from MD trajectories using standard macromolecular crystallography methods. In one set of simulations, harmonic restraints were applied to bias the protein structure toward the crystal structure. For these simulations, the recall of crystallographic waters using strong peaks in the MD water electron density was excellent, and there also was substantial visual agreement between the boomerang-like wings of the neutron density and the crystalline water hydrogen positions. An unrestrained simulation also was performed. For this simulation, the recall of crystallographic waters was much lower. The results demonstrate that it is now possible to recover crystallographic water structure using restrained MD simulations, but that it is not yet reasonable to expect unrestrained MD simulations to do the same. Further development and generalization of MD water models for force field development, macromolecular crystallography, and medicinal chemistry applications is now warranted. In particular, the combination of room-temperature crystallography, neutron diffraction, and crystalline MD simulations promises to substantially advance modeling of biomolecular solvation.

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

10.26434/chemrxiv.13265519 ◽

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."

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

10.26434/chemrxiv.13265519.v1 ◽

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

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Fragment Pose Prediction Using Non-Equilibrium Candidate Monte Carlo and Molecular Dynamics Simulations

10.26434/chemrxiv.10032218 ◽

2019 ◽

Author(s):

Nathan M. Lim ◽

Meghan Osato ◽

Gregory L. Warren ◽

David L. Mobley

Keyword(s):

Crystal Structure ◽

Molecular Dynamics ◽

Monte Carlo ◽

Ligand Binding ◽

Md Simulations ◽

Binding Mode ◽

Protein Crystal ◽

Pose Prediction ◽

Binding Modes ◽

Non Equilibrium

<div>Part of early stage drug discovery involves determining how molecules may bind to the target protein. Through understanding where and how molecules bind, chemists can begin to build ideas on how to design improvements to increase binding affinities. In this retrospective study, we compare how computational approaches like docking, molecular dynamics (MD) simulations, and a non-equilibrium candidate Monte Carlo (NCMC) based method (NCMC+MD) perform in predicting binding modes for a set of 12 fragment-like molecules which bind to soluble epoxide hydrolase. We evaluate each method's effectiveness in identifying the dominant binding mode and finding any additional binding modes (if any). Then, we compare our predicted binding modes to experimentally obtained X-ray crystal structures.</div><div>We dock each of the 12 small molecules into the apo-protein crystal structure and then run simulations up to 1 microsecond each. Small and fragment-like molecules likely have smaller energy barriers separating different binding modes by virtue of relatively fewer and weaker interactions relative to drug-like molecules, and thus likely undergo more rapid binding mode transitions. We expect, thus, to see more rapid transitions betweeen binding modes in our study. </div><div><br></div><div>Following this, we build Markov State Models (MSM) to define our stable ligand binding modes. We investigate if adequate sampling of ligand binding modes and transitions between them can occur at the microsecond timescale using traditional MD or a hybrid NCMC+MD simulation approach. Our findings suggest that even with small fragment-like molecules, we fail to sample all the crystallographic binding modes using microsecond MD simulations, but using NCMC+MD we have better success in sampling the crystal structure while obtaining the correct populations.</div>

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Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors

Science ◽

10.1126/science.abb3405 ◽

2020 ◽

Vol 368 (6489) ◽

pp. 409-412 ◽

Cited By ~ 468

Author(s):

Linlin Zhang ◽

Daizong Lin ◽

Xinyuanyuan Sun ◽

Ute Curth ◽

Christian Drosten ◽

...

Keyword(s):

Crystal Structure ◽

Severe Acute Respiratory Syndrome ◽

Drug Target ◽

Essential Role ◽

Potent Inhibitor ◽

Amide Bond ◽

Lead Compound ◽

X Ray ◽

Main Protease

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (Mpro, also called 3CLpro) because of its essential role in processing the polyproteins that are translated from the viral RNA. We report the x-ray structures of the unliganded SARS-CoV-2 Mpro and its complex with an α-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. On the basis of the unliganded structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 Mpro. The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.

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