Deciphering PD1 activation mechanism from molecular docking and molecular dynamic simulations

AbstractThe activation of T cells is normally accompanied by inhibitory mechanisms within which the PD1 receptor stands out. Upon binding the ligands PDL1 and PDL2, PD1 drives T cells to an unresponsive state called exhaustion characterized by a markedly decreased capacity to exert effector functions. For this reason, PD1 has become one of the most important targets in cancer immunotherapy. Despite the numerous studies about PD1 signaling modulation, how the PD1 signaling is activated upon the ligands’ binding remains an open question. Several experimental facts suggest that the activation of the PD1-PLD1 pathway depends on the interaction with an unknown partner at the cellular membrane. In this work, we investigate the possibility that the target of PD1-PDL1 is the same PD1-PDL1 complex. We combined molecular docking to explore different binding modes with molecular dynamics and umbrella sampling simulations to assess the complexes’ stability. We found a high molecular weight complex that explains the activation of PD1 upon PDL1 binding. This complex has an affinity comparable to the PD1-PDL1 interaction and resembles the form of a linear lattice.

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Characterizing the interaction modes of PAR4 receptor with agonist and antagonist by molecular simulation approach

Journal of Theoretical and Computational Chemistry ◽

10.1142/s0219633619500081 ◽

2019 ◽

Vol 18 (02) ◽

pp. 1950008

Author(s):

Nan Lu ◽

Fancui Meng ◽

Jing Yuan ◽

Lei Liu ◽

Yanshi Wang ◽

...

Keyword(s):

Conformational Changes ◽

Molecular Design ◽

Binding Free Energy ◽

Structural Characteristics ◽

Principal Component ◽

Activation Mechanism ◽

Binding Modes ◽

Dynamic Simulations ◽

Extracellular Region ◽

Agonist And Antagonist

Protease-activated receptor 4 (PAR4) is a promising target for antiplatelet therapy. In this study, homology modeling and molecular docking methods were used to investigate the binding modes of PAR4 agonists and antagonists. The outcomes show that agonists have good docking scores, and they also form more hydrogen bonds with PAR4 than antagonists. To reveal the different conformational changes caused by agonist and antagonist, molecular dynamic simulations were carried out on three selected PAR4 systems. Simulation results show that PAR4 activation involves breaking interactions of 3–7 lock switch (Try157 and Tyr322) and ionic lock switch (Arg188 and Asp173), and formation of transmission switch among Tyr161, Asn300 and Phe296. In addition, principal component analysis (PCA) indicates that the major change for agonist bound system takes place in the intracellular region while that for antagonist bound system is in the extracellular region. The binding free energy of BMS-986120 is much lower than AYPGKF, suggesting high affinity of antagonist. Moreover, the electronegative aspartic residues Asp230 and Asp235 at ECL2 are important for PAR4 binding to agonist. Clarifying the PAR4 structural characteristics may be helpful to understand the activation mechanism, giving insights into the molecular design and discovery of novel potential PAR4 antagonists in the future.

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Structural Insights into Sphingosine-1-phosphate Receptor Activation

10.1101/2022.01.15.475352 ◽

2022 ◽

Author(s):

Leiye Yu ◽

Licong He ◽

Bing Gan ◽

Rujuan Ti ◽

Qingjie Xiao ◽

...

Keyword(s):

Transition Process ◽

Receptor Activation ◽

Activation Mechanism ◽

Structural Basis ◽

Lymphoid Tissues ◽

Binding Modes ◽

Dynamic Simulations ◽

S1p Receptors ◽

Sphingosine 1 Phosphate ◽

Key Steps

As a critical sphingolipid metabolite, sphingosine-1-phosphate (S1P) plays an essential role in immune and vascular systems. There are five S1P receptors, designated as S1PR1-5, encoded in the human genome, and their activities are governed by endogenous S1P, lipid-like S1P mimics, or non-lipid-like therapeutic molecules. Among S1PRs, S1PR1 stands out due to its non-redundant functions, such as the egress of T and B cells from the thymus and secondary lymphoid tissues, making it a potential therapeutic target. However, the structural basis of S1PR1 activation and regulation by various agonists remains unclear. Here we reported four atomic resolution cryo-EM structures of Gi-coupled human S1PR1 complexes: bound to endogenous agonist d18:1 S1P, benchmark lipid-like S1P mimic phosphorylated Fingolimod ((S)-FTY720-P), or non-lipid-like therapeutic molecule CBP-307 in two binding modes. Our results revealed the similarities and differences of activation of S1PR1 through distinct ligands binding to the amphiphilic orthosteric pocket. We also proposed a two-step "shallow to deep" transition process of CBP-307 for S1PR1 activation. Both binding modes of CBP-307 could activate S1PR1, but from shallow to deep transition may trigger the rotation of the N-terminal helix of Gαi and further stabilize the complex by increasing the Gαi interaction with the cell membrane. We combine with extensive biochemical analysis and molecular dynamic simulations to suggest key steps of S1P binding and receptor activation. The above results decipher the common feature of the S1PR1 agonist recognition and activation mechanism and will firmly promote the development of therapeutics targeting S1P receptors.

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Exploration of cyclooxygenase-1 binding modes of some chiral anti-inflammatory drugs using molecular docking and dynamic simulations

International Journal of Computational Biology and Drug Design ◽

10.1504/ijcbdd.2019.10022513 ◽

2019 ◽

Vol 12 (3) ◽

pp. 281

Author(s):

Safia Kellou Tairi ◽

Zohra Bouakouk ◽

Meriem Meyar ◽

Samira Feddal

Keyword(s):

Molecular Docking ◽

Binding Modes ◽

Dynamic Simulations ◽

Cyclooxygenase 1 ◽

Inflammatory Drugs ◽

Anti Inflammatory

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Molecular Docking and Dynamics Simulation Study on the Influence of Zn2+ on the Binding Modes of Aggrecanase with its Inhibitors

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207317666141113155141 ◽

2015 ◽

Vol 17 (10) ◽

pp. 891-903 ◽

Cited By ~ 1

Author(s):

Panneer Suganya ◽

Sukesh kalva ◽

Lilly Saleena

Keyword(s):

Molecular Docking ◽

Simulation Study ◽

Dynamics Simulation ◽

Binding Modes ◽

Molecular Docking And Dynamics

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A New Series Of 1,3-Dimethylxanthine Based Adenosine A2a Receptor Antagonists As A Non-Dopaminergic Treatment Of Parkinson’s Disease

Current Drug Discovery Technologies ◽

10.2174/1570163817666200827112252 ◽

2020 ◽

Vol 17 ◽

Author(s):

Suman Rohilla ◽

Ranju Bansal ◽

Puneet Chauhan ◽

Sonja Kachler ◽

Karl-Norbert Klotz

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Molecular Docking ◽

Binding Affinity ◽

Docking Studies ◽

Binding Modes ◽

Molecular Docking Studies ◽

In Silico Docking ◽

Adenosine A2a Receptor Antagonists ◽

The Impact

Background: Adenosine receptors (AR) have emerged as competent and innovative nondopaminergic targets for the development of potential drug candidates and thus constitute an effective and safer treatment approach for Parkinson’s disease (PD). Xanthine derivatives are considered as potential candidates for the treatment Parkinson’s disease due to their potent A2A AR antagonistic properties. Objective: The objectives of the work are to study the impact of substituting N7-position of 8-m/pchloropropoxyphenylxanthine structure on in vitro binding affinity of compounds with various AR subtypes, in vivo antiparkinsonian activity and binding modes of newly synthesized xanthines with A2A AR in molecular docking studies. Methods: Several new 7-substituted 8-m/p-chloropropoxyphenylxanthine analogues have been prepared. Adenosine receptor binding assays were performed to study the binding interactions with various subtypes and perphenazine induced rat catatonia model was used for antiparkinsonian activity. Molecular docking studies were performed using Schrödinger molecular modeling interface. Results: 8-para-substituted xanthine 9b bearing an N7-propyl substituent displayed the highest affinity towards A2A AR (Ki = 0.75 µM) with moderate selectivity versus other AR subtypes. 7-Propargyl analogue 9d produced significantly longlasting antiparkinsonian effects and also produced potent and selective binding affinity towards A2A AR. In silico docking studies further highlighted the crucial structural components required to develop xanthine derived potential A2A AR ligands as antiparkinsonian agents. Conclusion: A new series of 7-substituted 8-m/p-chloropropoxyphenylxanthines having good affinity for A2A AR and potent antiparkinsonian activity has been developed.

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Discovery of New Inhibitors of Transforming Growth Factor-Beta Type 1 Receptor by Utilizing Docking and Structure-Activity Relationship Analysis

International Journal of Molecular Sciences ◽

10.3390/ijms20174090 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4090 ◽

Cited By ~ 3

Author(s):

Jiang ◽

Deng

Keyword(s):

Molecular Docking ◽

Growth Factor ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Binding Modes ◽

Structure Activity Relationships ◽

Structure Activity ◽

Growth Factor Beta ◽

New Compounds

The transforming growth factor-beta (TGF-β) plays an important role in pathological fibrosis and cancer transformation. Therefore, the inhibition of the TGF-β signaling pathway has therapeutic potential in the treatment of cancer. In this study, the binding modes between 47 molecules with a pyrrolotriazine-like backbone structure and transforming growth factor-beta type 1 receptor (TβR1) were simulated by molecular docking using Discovery Studio software, and their structure–activity relationships were analyzed. On the basis of the analysis of the binding modes of ligands in the active site and the structure–activity relationships, 29,254 new compounds were designed for virtual screening. According to the aforementioned analyses and Lipinski’s rule of five, five new compounds (CQMU1901–1905) with potential activity were screened through molecular docking. Among them, CQMU1905 is an attractive molecule composed of 5-fluorouracil (5-FU), 6-mercaptopurine (6-MP), and 5-azacytosine. Interestingly, 5-FU, 6-MP, and 5-azacytidine are often used as anti-metabolic agents in cancer treatment. Compared with existing compounds, CQMU1901–1905 can interact with target proteins more effectively and have good potential for modification, making them worthy of further study.

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Study of Endogen Substrates, Drug Substrates and Inhibitors Binding Conformations on MRP4 and Its Variants by Molecular Docking and Molecular Dynamics

Molecules ◽

10.3390/molecules26041051 ◽

2021 ◽

Vol 26 (4) ◽

pp. 1051

Author(s):

Edgardo Becerra ◽

Giovanny Aguilera-Durán ◽

Laura Berumen ◽

Antonio Romo-Mancillas ◽

Guadalupe García-Alcocer

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Binding Energy ◽

Binding Site ◽

Binding Sites ◽

Adenosine Monophosphate ◽

Competitive Inhibitor ◽

Umbrella Sampling ◽

Coarse Grained ◽

Nucleotide Polymorphisms

Multidrug resistance protein-4 (MRP4) belongs to the ABC transporter superfamily and promotes the transport of xenobiotics including drugs. A non-synonymous single nucleotide polymorphisms (nsSNPs) in the ABCC4 gene can promote changes in the structure and function of MRP4. In this work, the interaction of certain endogen substrates, drug substrates, and inhibitors with wild type-MRP4 (WT-MRP4) and its variants G187W and Y556C were studied to determine differences in the intermolecular interactions and affinity related to SNPs using protein threading modeling, molecular docking, all-atom, coarse grained, and umbrella sampling molecular dynamics simulations (AA-MDS and CG-MDS, respectively). The results showed that the three MRP4 structures had significantly different conformations at given sites, leading to differences in the docking scores (DS) and binding sites of three different groups of molecules. Folic acid (FA) had the highest variation in DS on G187W concerning WT-MRP4. WT-MRP4, G187W, Y556C, and FA had different conformations through 25 ns AA-MD. Umbrella sampling simulations indicated that the Y556C-FA complex was the most stable one with or without ATP. In Y556C, the cyclic adenosine monophosphate (cAMP) and ceefourin-1 binding sites are located out of the entrance of the inner cavity, which suggests that both cAMP and ceefourin-1 may not be transported. The binding site for cAMP and ceefourin-1 is quite similar and the affinity (binding energy) of ceefourin-1 to WT-MRP4, G187W, and Y556C is greater than the affinity of cAMP, which may suggest that ceefourin-1 works as a competitive inhibitor. In conclusion, the nsSNPs G187W and Y556C lead to changes in protein conformation, which modifies the ligand binding site, DS, and binding energy.

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Interaction between DNA, Albumin and Apo-Transferrin and Iridium(III) Complexes with Phosphines Derived from Fluoroquinolones as a Potent Anticancer Drug

Pharmaceuticals ◽

10.3390/ph14070685 ◽

2021 ◽

Vol 14 (7) ◽

pp. 685

Author(s):

Sandra Amanda Kozieł ◽

Monika Katarzyna Lesiów ◽

Daria Wojtala ◽

Edyta Dyguda-Kazimierowicz ◽

Dariusz Bieńko ◽

...

Keyword(s):

Molecular Docking ◽

Serum Proteins ◽

Docking Study ◽

Minor Groove ◽

Docking Studies ◽

Minor Groove Binding ◽

Binding Modes ◽

Groove Binding ◽

Molecular Docking Study ◽

Threading Intercalation

A group of cytotoxic half-sandwich iridium(III) complexes with aminomethyl(diphenyl)phosphine derived from fluoroquinolone antibiotics exhibit the ability to (i) accumulate in the nucleus, (ii) induce apoptosis, (iii) activate caspase-3/7 activity, (iv) induce the changes in cell cycle leading to G2/M phase arrest, and (v) radicals generation. Herein, to elucidate the cytotoxic effects, we investigated the interaction of these complexes with DNA and serum proteins by gel electrophoresis, fluorescence spectroscopy, circular dichroism, and molecular docking studies. DNA binding experiments established that the complexes interact with DNA by moderate intercalation and predominance of minor groove binding without the capability to cause a double-strand cleavage. The molecular docking study confirmed two binding modes: minor groove binding and threading intercalation with the fluoroquinolone part of the molecule involved in pi stacking interactions and the Ir(III)-containing region positioned within the major or minor groove. Fluorescence spectroscopic data (HSA and apo-Tf titration), together with molecular docking, provided evidence that Ir(III) complexes can bind to the proteins in order to be transferred. All the compounds considered herein were found to bind to the tryptophan residues of HSA within site I (subdomain II A). Furthermore, Ir(III) complexes were found to dock within the apo-Tf binding site, including nearby tyrosine residues.

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