A human ether-á-go-go-related (hERG) ion channel atomistic model generated by long supercomputer molecular dynamics simulations and its use in predicting drug cardiotoxicity

Anwar-Mohamed, Anwar; Barakat, Khaled; Bhat, Rakesh; Noskov, Sergei Y.; Tyrrell, D. Lorne; Tuszyński, Jack A.; Houghton, Michael

doi:10.1016/j.toxlet.2014.08.007

Cited by 48 publications

(40 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…More importantly, the resulting MD trajectories allowed us to accurately measure the binding affinities for the predicted complexes using the molecular mechanic-Poisson Boltzmann surface area (MM-PBSA) method [21][22][23][24][25][26][27][28]. The MM-PBSA method has been successfully applied in several drug design related studies [35][36][37][38][39][40][41][42]. We also included for this analysis two models of PD-1/PD-L1 and PD1/PD-L2 that were constructed by superimposing the human PD-1, PD-L1 and PD-L2 on the reported mouse crystal structures for each protein-protein complex similar to the same procedure as described in Cheng's study [20].…”

Section: Refining the Docked Structures And Their Final Rankingmentioning

confidence: 99%

Human PD-1 binds differently to its human ligands: A comprehensive modeling study

Viricel

Ahmed

Barakat

2015

Journal of Molecular Graphics and Modelling

View full text Add to dashboard Cite

Section: Refining the Docked Structures And Their Final Rankingmentioning

confidence: 99%

Human PD-1 binds differently to its human ligands: A comprehensive modeling study

Viricel

Ahmed

Barakat

2015

Journal of Molecular Graphics and Modelling

View full text Add to dashboard Cite

“…With this limitation, molecular modelling and computer simulations can offer a comprehensive and alternative approach to understand these interactions [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] . Although there have been previous attempts to model the hPD-1/hPD-L1 and hPD-1/hPD-L2 complexes, none of these models correlated well with available experimental data.…”

Section: Research Highlightmentioning

confidence: 99%

Baby Steps Toward Modelling The Full human Programmed Death-1 (PD-1) Pathway

Ahmed

Barakat

2015

Receptor Clin Invest

View full text Add to dashboard Cite

Immune checkpoints are vital elements in regulating the immune system. They preserve the immunological balance between preventing continuous activated immune responses and defending against chronic infections and cancer. Blocking the immune inhibitory checkpoints pathways recently emerged as a 'game changer' approach in cancer and antiviral immunotherapy. Modeling these pathways at the atomic level provides a key step toward rationally designing selective blockers for these pathways. Current crystal structures for the immune checkpoints are mainly not for human and are very limited in their scope of interactions. Our team has been focused on building atomistic models for these proteins, characterizing their protein-protein interactions and designing new inhibitory drugs for their activity. This article highlights our recent study on modelling the human Programmed Death-1 (hPD-1) pathway by characterizing the interactions between hPD-1 and its two human ligands. In this study, we showed that hPD1 binds differently to its two ligands. We also showed that the modes of binding for each ligand are different between mouse and human, emphasizing the limited information in current mouse crystal structures. Our findings enhanced the understanding of the receptor-ligand(s) interactions and formed a significant step toward building a full model for the whole PD1 pathway. This undoubtedly will foster the ongoing efforts to develop antibodies and small molecule drugs against this important T cell immune-regulatory mechanism.To cite this article: Marawan Ahmed, et al. Baby steps toward modelling the full human programmed Death-1 (PD-1) pathway. Receptor Clin Invest 2015; 2: e825.

show abstract

“…Another infamous example of very expensive drug development failure could be found in one of the most promising anti-retroviral agents BMS-986094 [5]. The lead molecule passed all regulatory stages and made it to the human clinical trials, but was discontinued due to severe cardiotoxicity, at least in part owing to highly specific interactions with cardiac ion channels[6, 7]. …”

Section: Introductionmentioning

confidence: 99%

Computational membrane biophysics: From ion channel interactions with drugs to cellular function

Miranda

Ngo

Perissinotti

et al. 2017

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

View full text Add to dashboard Cite

The rapid development of experimental and computational techniques has changed fundamentally our understanding of cellular-membrane transport. The advent of powerful computers and refined force-fields for proteins, ions, and lipids has expanded the applicability of Molecular Dynamics (MD) simulations. A myriad of cellular responses is modulated through the binding of endogenous and exogenous ligands (e.g. neurotransmitters and drugs, respectively) to ion channels. Deciphering the thermodynamics and kinetics of the ligand binding processes to these membrane proteins is at the heart of modern drug development. The ever-increasing computational power has already provided insightful data on the thermodynamics and kinetics of drug-target interactions, free energies of solvation, and partitioning into lipid bilayers for drugs. This review aims to provide a brief summary about modeling approaches to map out crucial binding pathways with intermediate conformations and free-energy surfaces for drug-ion channel binding mechanisms that are responsible for multiple effects on cellular functions. We will discuss post-processing analysis of simulation-generated data, which are then transformed to kinetic models to better understand the molecular underpinning of the experimental observables under the influence of drugs or mutations in ion channels. This review highlights crucial mathematical frameworks and perspectives on bridging different well-established computational techniques to connect the dynamics and timescales from all-atom MD and free energy simulations of ion channels to the physiology of action potentials in cellular models.

show abstract

A human ether-á-go-go-related (hERG) ion channel atomistic model generated by long supercomputer molecular dynamics simulations and its use in predicting drug cardiotoxicity

Cited by 48 publications

References 44 publications

Human PD-1 binds differently to its human ligands: A comprehensive modeling study

Human PD-1 binds differently to its human ligands: A comprehensive modeling study

Baby Steps Toward Modelling The Full human Programmed Death-1 (PD-1) Pathway

Computational membrane biophysics: From ion channel interactions with drugs to cellular function

Contact Info

Product

Resources

About