Deciphering the crucial residues involved in heterodimerization of Bak peptide and anti-apoptotic proteins for apoptosis

Marimuthu, Parthiban; Singaravelu, Kalaimathy

doi:10.1080/07391102.2017.1331863

Cited by 13 publications

(10 citation statements)

References 45 publications

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“…Previously, several studies have been carried out on different Bcl-2 family proteins using various MD simulation approaches. These investigations revealed (i) the driving force behind the intra-molecular conformational change [ 58 ], (ii) the helix stability [ 59 , 60 ], (iii) crucial residues involved in heterodimerization [ 61 ] (iv) crucial molecular properties responsible for complexity [ 62 , 63 , 64 ] (v) hot-spot residues [ 65 ] (vi) effects of Bim mutants [ 66 ] and (vii) the inter-helical interactions across families [ 67 ]. Based on this information, we attempted to explore the mMcl1—PAP complexes to extend our understanding of the molecular mechanism of heterodimerization by identifying the key features.…”

Section: Resultsmentioning

confidence: 99%

Predicted Hotspot Residues Involved in Allosteric Signal Transmission in Pro-Apoptotic Peptide—Mcl1 Complexes

et al. 2020

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Mcl1 is a primary member of the Bcl–2 family—anti–apoptotic proteins (AAP)—that is overexpressed in several cancer pathologies. The apoptotic regulation is mediated through the binding of pro-apoptotic peptides (PAPs) (e.g., Bak and Bid) at the canonical hydrophobic binding groove (CBG) of Mcl1. Although all PAPs form amphipathic α-helices, their amino acid sequences vary to different degree. This sequence variation exhibits a central role in the binding partner selectivity towards different AAPs. Thus, constructing a novel peptide or small organic molecule with the ability to mimic the natural regulatory process of PAP is essential to inhibit various AAPs. Previously reported experimental binding free energies (BFEs) were utilized in the current investigation aimed to understand the mechanistic basis of different PAPs targeted to mMcl1. Molecular dynamics (MD) simulations used to estimate BFEs between mMcl1—PAP complexes using Molecular Mechanics-Generalized Born Solvent Accessible (MMGBSA) approach with multiple parameters. Predicted BFE values showed an excellent agreement with the experiment (R2 = 0.92). The van–der Waals (ΔGvdw) and electrostatic (ΔGele) energy terms found to be the main energy components that drive heterodimerization of mMcl1—PAP complexes. Finally, the dynamic network analysis predicted the allosteric signal transmission pathway involves more favorable energy contributing residues. In total, the results obtained from the current investigation may provide valuable insights for the synthesis of a novel peptide or small organic inhibitor targeting Mcl1.

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Section: Resultsmentioning

confidence: 99%

Predicted Hotspot Residues Involved in Allosteric Signal Transmission in Pro-Apoptotic Peptide—Mcl1 Complexes

et al. 2020

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“…In our previous investigation, MD simulation was widely applied to Bcl-2 family proteins to gain an understanding on the mechanism of action [37,39,40,56]. Likewise, the current study is an attempt to extend our understanding of the molecular mechanism of Mcl1 with the highly active compound from the dataset-C40-used to construct the 3D-QSAR model.…”

Section: Simulations Of Docked Complexmentioning

confidence: 99%

Investigating the Molecular Basis of N-Substituted 1-Hydroxy-4-Sulfamoyl-2-Naphthoate Compounds Binding to Mcl1

2019

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Myeloid cell leukemia-1 (Mcl1) is an anti–apoptotic protein that has gained considerable attention due to its overexpression activity prevents cell death. Therefore, a potential inhibitor that specifically targets Mcl1 with higher binding affinity is necessary. Recently, a series of N-substituted 1-hydroxy-4-sulfamoyl-2-naphthoate compounds was reported that targets Mcl1, but its binding mechanism remains unexplored. Here, we attempted to explore the molecular mechanism of binding to Mcl1 using advanced computational approaches: pharmacophore-based 3D-QSAR, docking, and MD simulation. The selected pharmacophore—NNRRR—yielded a statistically significant 3D-QSAR model containing high confidence scores (R2 = 0.9209, Q2 = 0.8459, and RMSE = 0.3473). The contour maps—comprising hydrogen bond donor, hydrophobic, negative ionic and electron withdrawal effects—from our 3D-QSAR model identified the favorable regions crucial for maximum activity. Furthermore, the external validation of the selected model using enrichment and decoys analysis reveals a high predictive power. Also, the screening capacity of the selected model had scores of 0.94, 0.90, and 8.26 from ROC, AUC, and RIE analysis, respectively. The molecular docking of the highly active compound—C40; 4-(N-benzyl-N-(4-(4-chloro-3,5-dimethylphenoxy) phenyl) sulfamoyl)-1-hydroxy-2-naphthoate—predicted the low-energy conformational pose, and the MD simulation revealed crucial details responsible for the molecular mechanism of binding with Mcl1.

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“…The MM-PB(GB)SA approach has been applied in a number of studies, including the development of anticancer compounds [222][223][224], antibacterial [225][226][227], antiviral [228][229][230][231][232] and antiparasitic drugs [233][234][235], as well as antipsychotics [236,237]. These methods are also often applied to understand and analyze the binding mode and key interactions of small molecules [238,239] as well as peptide [240,241] and protein ligands [242] at their targets. Several comparative studies differentiating between the prediction accuracy of ∆G bind energies of protein-ligand complexes by MM-GBSA and MM-PBSA have been reported [243][244][245][246].…”

Section: Binding Energy Estimationmentioning

confidence: 99%

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

et al. 2020

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Molecular dynamics (MD) simulations have become increasingly useful in the modern drug development process. In this review, we give a broad overview of the current application possibilities of MD in drug discovery and pharmaceutical development. Starting from the target validation step of the drug development process, we give several examples of how MD studies can give important insights into the dynamics and function of identified drug targets such as sirtuins, RAS proteins, or intrinsically disordered proteins. The role of MD in antibody design is also reviewed. In the lead discovery and lead optimization phases, MD facilitates the evaluation of the binding energetics and kinetics of the ligand-receptor interactions, therefore guiding the choice of the best candidate molecules for further development. The importance of considering the biological lipid bilayer environment in the MD simulations of membrane proteins is also discussed, using G-protein coupled receptors and ion channels as well as the drug-metabolizing cytochrome P450 enzymes as relevant examples. Lastly, we discuss the emerging role of MD simulations in facilitating the pharmaceutical formulation development of drugs and candidate drugs. Specifically, we look at how MD can be used in studying the crystalline and amorphous solids, the stability of amorphous drug or drug-polymer formulations, and drug solubility. Moreover, since nanoparticle drug formulations are of great interest in the field of drug delivery research, different applications of nano-particle simulations are also briefly summarized using multiple recent studies as examples. In the future, the role of MD simulations in facilitating the drug development process is likely to grow substantially with the increasing computer power and advancements in the development of force fields and enhanced MD methodologies.

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Deciphering the crucial residues involved in heterodimerization of Bak peptide and anti-apoptotic proteins for apoptosis

Cited by 13 publications

References 45 publications

Predicted Hotspot Residues Involved in Allosteric Signal Transmission in Pro-Apoptotic Peptide—Mcl1 Complexes

Predicted Hotspot Residues Involved in Allosteric Signal Transmission in Pro-Apoptotic Peptide—Mcl1 Complexes

Investigating the Molecular Basis of N-Substituted 1-Hydroxy-4-Sulfamoyl-2-Naphthoate Compounds Binding to Mcl1

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

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