Hydrophobic Interactions Are a Key to MDM2 Inhibition by Polyphenols as Revealed by Molecular Dynamics Simulations and MM/PBSA Free Energy Calculations

Verma, Subhash; Grover, Sonam; Tyagi, Chetna; Goyal, Sukriti; Jamal, Salma; Singh, Aditi; Grover, Abhinav

doi:10.1371/journal.pone.0149014

Cited by 74 publications

(60 citation statements)

References 42 publications

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“…The MMPBSA is a method which is currently used to estimate the binding free energy [41]. Snapshots were extracted at every 50 ps of stable intervals from 80-100 ns MD trajectory.…”

Section: The Binding Energy Of S100a8/a9 Subunits In Presence Of Aa/omentioning

confidence: 99%

Effects of unsaturated fatty acids (Arachidonic/Oleic Acids) on stability and structural properties of Calprotectin using molecular docking and molecular dynamics simulation approach

et al. 2020

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Calprotectin is a heterodimeric protein complex with two subunits called S100A8/A9. The protein has an essential role in inflammation process and various human diseases. It has the ability to bind to unsaturated fatty acids including Arachidonic acid, Oleic acid and etc., which could be considered as a major carrier for fatty acids. In this study we aimed to appraise the thermodynamics and structural changes of Calprotectin in presence of Arachidonic acid/Oleic acid) using docking and molecular dynami simulation method. To create the best conformation of Calprotectin-Oleic acid/Arachidonic acid complexes, the docking process was performed. The complexes with the best binding energy were selected as the models for molecular dynamics simulation process. Furthermore, the structural and thermodynamics properties of the complexes were evaluated too. The Root Mean Square Deviation and Root Mean Square Fluctuation results showed that the binding of Arachidonic acid/ Oleic acid to Calprotectin can cause the protein structural changes which was confirmed by Define Secondary Structure of Proteins results. Accordingly, the binding free energy results verified that binding of Oleic acid to Calprotectin leads to instability of S100A8/A9 subunits in the protein. Moreover, the electrostatic energy contribution of the complexes (Calprotectin-Oleic acid/Arachidonic acid) was remarkably higher than van der Waals energy. Thus, the outcome of this study confirm that Oleic acid has a stronger interaction with Calprotectin in comparison with Arachidonic acid. Our findings indicated that binding of unsaturated fatty acids to Calprotectin leads to structural changes of the S100A8/A9 subunits which could be beneficial to play a biological role in inflammation process.

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“…The MMPBSA is a method which is currently used to estimate the binding free energy [41]. Snapshots were extracted at every 50 ps of stable intervals from 80-100 ns MD trajectory.…”

Section: The Binding Energy Of S100a8/a9 Subunits In Presence Of Aa/omentioning

confidence: 99%

Effects of unsaturated fatty acids (Arachidonic/Oleic Acids) on stability and structural properties of Calprotectin using molecular docking and molecular dynamics simulation approach

et al. 2020

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“…In terms of negative contribution, van der Waals interaction gives much larger contribution than electrostatic interactions for all the cases. The non-polar free energy contributes relatively less as compared to the total binding energy (Verma et al, 2016). This indicates that non-polar solvation energy, van der Waals, and electrostatic interaction together contribute to the SEI-HDAC4 complex stability.…”

Section: Resultsmentioning

confidence: 99%

Mechanistic Insights into the Binding of Class IIa HDAC Inhibitors toward Spinocerebellar Ataxia Type-2: A 3D-QSAR and Pharmacophore Modeling Approach

et al. 2017

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Spinocerebellar ataxia (SCA-2) type-2 is a rare neurological disorder among the nine polyglutamine disorders, mainly caused by polyQ (CAG) trinucleotide repeats expansion within gene coding ataxin-2 protein. The expanded trinucleotide repeats within the ataxin-2 protein sequesters transcriptional cofactors i.e., CREB-binding protein (CBP), Ataxin-2 binding protein 1 (A2BP1) leading to a state of hypo-acetylation and transcriptional repression. Histone de-acetylases inhibitors (HDACi) have been reported to restore transcriptional balance through inhibition of class IIa HDAC's, that leads to an increased acetylation and transcription as demonstrated through in-vivo studies on mouse models of Huntington's. In this study, 61 di-aryl cyclo-propanehydroxamic acid derivatives were used for developing three dimensional (3D) QSAR and pharmacophore models. These models were then employed for screening and selection of anti-ataxia compounds. The chosen QSAR model was observed to be statistically robust with correlation coefficient (r2) value of 0.6774, cross-validated correlation coefficient (q2) of 0.6157 and co-relation coefficient for external test set (pred_r2) of 0.7570. A high F-test value of 77.7093 signified the robustness of the model. Two potential drug leads ZINC 00608101 (SEI) and ZINC 00329110 (ACI) were selected after a coalesce procedure of pharmacophore based screening using the pharmacophore model ADDRR.20 and structural analysis using molecular docking and dynamics simulations. The pharmacophore and the 3D-QSAR model generated were further validated for their screening and prediction ability using the enrichment factor (EF), goodness of hit (GH), and receiver operating characteristics (ROC) curve analysis. The compounds SEI and ACI exhibited a docking score of −10.097 and −9.182 kcal/mol, respectively. An evaluation of binding conformation of ligand-bound protein complexes was performed with MD simulations for a time period of 30 ns along with free energy binding calculations using the g_mmpbsa technique. Prediction of inhibitory activities of the two lead compounds SEI (7.53) and ACI (6.84) using the 3D-QSAR model reaffirmed their inhibitory characteristics as potential anti-ataxia compounds.

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“…Ligand topologies and coordinates were generated by PRODRG program . The system was simulated in step by step manner as discussed in detail in our earlier …”

Section: Methodsmentioning

confidence: 99%

Structural insights into impact of Y134F mutation and discovery of novel fungicidal compounds against CYP51 in Puccinia triticina

Pandey

Sharma

2017

J of Cellular Biochemistry

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Sterol 14α-Demethylase Cytochrome P450 (CYP51) protein involved in ergosterol biosynthesis pathways turn out to be a crucial target for the fungicidal compound. However, the recognition mechanism and dynamic behavior of CYP51 in wheat leaf rust pathogen, Puccinia triticina, is still obscure. Previously, a mutation at position 134 (Y134F) was reported in five European isolates of P. triticina, conversely, structural basis of this mutation remains unclear. To address this problem, three-dimensional structure of CYP51 protein from P. triticina was successfully built using homology modeling approach. To assess the protein structure stability, wild and mutant-type CYP51 proteins bound with azole fungicide was subjected to 50 ns molecular dynamics (MD) simulations run. Observably, the comparative protein-ligand interaction analysis and binding free energy results revealed that impact of the mutation on the thermodynamics and conformational stability of the CYP51 protein was negligible. In addition, we carried out structure-based virtual screening and identified potent novel fungicidal compounds from four different databases and libraries. Consequently, through MD simulation and thermodynamic integration, four novel compounds such as CoCoCo54211 (CoCoCo database), ZINC04089470 (ZINC database), Allyl pyrocatechol 3,4 diacetate (Natural compound library), and 9-octadecenoic acid (Traditional Chinese Medicine database) has been predicted as potent fungicidal compound against CYP51 with XPGlide docking score of -11.41, -13.64, -7.40, and -6.55 kcal/mol, respectively. These compounds were found to form hydrogen bonds with heme group of CYP51, subsequently disturbing the stability and survival of fungus and can be used to control leaf rust in wheat.

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Hydrophobic Interactions Are a Key to MDM2 Inhibition by Polyphenols as Revealed by Molecular Dynamics Simulations and MM/PBSA Free Energy Calculations

Cited by 74 publications

References 42 publications

Effects of unsaturated fatty acids (Arachidonic/Oleic Acids) on stability and structural properties of Calprotectin using molecular docking and molecular dynamics simulation approach

Effects of unsaturated fatty acids (Arachidonic/Oleic Acids) on stability and structural properties of Calprotectin using molecular docking and molecular dynamics simulation approach

Mechanistic Insights into the Binding of Class IIa HDAC Inhibitors toward Spinocerebellar Ataxia Type-2: A 3D-QSAR and Pharmacophore Modeling Approach

Structural insights into impact of Y134F mutation and discovery of novel fungicidal compounds against CYP51 in Puccinia triticina

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