Molecular Dynamics Simulation Framework to Probe the Binding Hypothesis of CYP3A4 Inhibitors

Kiani, Yusra Sajid; Ranaghan, Kara E.; Jabeen, Ishrat; Mulholland, Adrian J.

doi:10.3390/ijms20184468

Cited by 20 publications

(14 citation statements)

References 106 publications

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“…The wild-type pocket volume range of CYP3A5 calculated in our study confirmed such property. Our results also show higher pocket volume values reported previously for CYP3A4 evaluated to 1386 Å 3 and 520 Å 3 from two different studies [36]. These values, however, were reported based on single-point calculations for the unbound structure of CYP3A4.…”

Section: Catalytic Pocket Volume Calculationsupporting

confidence: 69%

Single Nucleotide Polymorphism Induces Divergent Dynamic Patterns in CYP3A5: A Microsecond Scale Biomolecular Simulation of Variants Identified in Sub-Saharan African Populations

Othman

Rocha

Hazelhurst

2021

IJMS

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Pharmacogenomics aims to reveal variants associated with drug response phenotypes. Genes whose roles involve the absorption, distribution, metabolism, and excretion of drugs, are highly polymorphic between populations. High coverage whole genome sequencing showed that a large proportion of the variants for these genes are rare in African populations. This study investigated the impact of such variants on protein structure to assess their functional importance. We used genetic data of CYP3A5 from 458 individuals from sub-Saharan Africa to conduct a structural bioinformatics analysis. Five missense variants were modeled and microsecond scale molecular dynamics simulations were conducted for each, as well as for the CYP3A5 wildtype and the Y53C variant, which has a known deleterious impact on enzyme activity. The binding of ritonavir and artemether to CYP3A5 variant structures was also evaluated. Our results showed different conformational characteristics between all the variants. No significant structural changes were noticed. However, the genetic variability seemed to act on the plasticity of the protein. The impact on drug binding might be drug dependant. We concluded that rare variants hold relevance in determining the pharmacogenomics properties of populations. This could have a significant impact on precision medicine applications in sub-Saharan Africa.

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Section: Catalytic Pocket Volume Calculationsupporting

confidence: 69%

Single Nucleotide Polymorphism Induces Divergent Dynamic Patterns in CYP3A5: A Microsecond Scale Biomolecular Simulation of Variants Identified in Sub-Saharan African Populations

Othman

Rocha

Hazelhurst

2021

IJMS

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“…Morever, calpain inhibitors and GC-376 analogs are also confirmed to accommodate in the same functional pocket [ 58 ]. Beside these, many in silico studies have demonstrated the binding affinity of drug molecules to this active side of Mpro [ 33 , 59 , 60 , 61 ].…”

Section: Resultsmentioning

confidence: 99%

Computational Determination of Potential Multiprotein Targeting Natural Compounds for Rational Drug Design Against SARS-COV-2

et al. 2021

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SARS-CoV-2 caused the current COVID-19 pandemic and there is an urgent need to explore effective therapeutics that can inhibit enzymes that are imperative in virus reproduction. To this end, we computationally investigated the MPD3 phytochemical database along with the pool of reported natural antiviral compounds with potential to be used as anti-SARS-CoV-2. The docking results demonstrated glycyrrhizin followed by azadirachtanin, mycophenolic acid, kushenol-w and 6-azauridine, as potential candidates. Glycyrrhizin depicted very stable binding mode to the active pocket of the Mpro (binding energy, −8.7 kcal/mol), PLpro (binding energy, −7.9 kcal/mol), and Nucleocapsid (binding energy, −7.9 kcal/mol) enzymes. This compound showed binding with several key residues that are critical to natural substrate binding and functionality to all the receptors. To test docking prediction, the compound with each receptor was subjected to molecular dynamics simulation to characterize the molecule stability and decipher its possible mechanism of binding. Each complex concludes that the receptor dynamics are stable (Mpro (mean RMSD, 0.93 Å), PLpro (mean RMSD, 0.96 Å), and Nucleocapsid (mean RMSD, 3.48 Å)). Moreover, binding free energy analyses such as MMGB/PBSA and WaterSwap were run over selected trajectory snapshots to affirm intermolecular affinity in the complexes. Glycyrrhizin was rescored to form strong affinity complexes with the virus enzymes: Mpro (MMGBSA, −24.42 kcal/mol and MMPBSA, −10.80 kcal/mol), PLpro (MMGBSA, −48.69 kcal/mol and MMPBSA, −38.17 kcal/mol) and Nucleocapsid (MMGBSA, −30.05 kcal/mol and MMPBSA, −25.95 kcal/mol), were dominated mainly by vigorous van der Waals energy. Further affirmation was achieved by WaterSwap absolute binding free energy that concluded all the complexes in good equilibrium and stability (Mpro (mean, −22.44 kcal/mol), PLpro (mean, −25.46 kcal/mol), and Nucleocapsid (mean, −23.30 kcal/mol)). These promising findings substantially advance our understanding of how natural compounds could be shaped to counter SARS-CoV-2 infection.

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“…The involvement of serine here is not unexpected as the implicated iminium ion species is a hard electrophile and will preferentially react with a nucleophile of comparable 'hardness' such as the hydroxyl groups of serine residues (LoPachin and DeCaprio, 2005). Additionally, the possibility of this serine residue being implicated in its MBI is further reinforced by a recent study which identified Ser312 in CYP3A4 as an important binding site residue implicated in ligand inhibitory interactions (Kiani et al, 2019).…”

Section: Discussionmentioning

confidence: 74%

Direct and Sequential Bioactivation of Pemigatinib to Reactive Iminium Ion Intermediates Culminates in Mechanism-Based Inactivation of Cytochrome P450 3A

et al. 2022

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We recently established the mechanism-based inactivation (MBI) of cytochrome P450 3A (CYP3A) by the fibroblast growth factor receptor (FGFR) inhibitors erdafitinib and infigratinib. Serendipitously, our preliminary data has also revealed that pemigatinib (PEM)another clinically approved FGFR1-3 inhibitorsimilarly elicited time-dependent inhibition of CYP3A. This was rather unexpected as it was previously purported that PEM did not pose any metabolism-dependent liabilities due to the absence of glutathione-related conjugates in metabolic profiling experiments conducted in human liver microsomes. Here, we confirmed that PEM inhibited both CYP3A isoforms in a time-, concentration-, and cofactor-dependent manner consistent with MBIwith K I , k inact , and partition ratio of 8.69 and 11.95 μM, 0.108 and 0.042 min −1 , and ~44 and ~47 for CYP3A4 and CYP3A5 respectively. While the rate of inactivation was diminished by coincubation with an alternative substrate or direct inhibitor of CYP3A, the inclusion of nucleophilic trapping agents afforded no such protection. Furthermore, the lack of catalytic activity recovery following dialysis and oxidation with potassium ferricyanide coupled with the absence of a spectrally resolvable peak in the Soret region collectively implied that the underlying mechanism of inactivation was not elicited via the formation of pseudo-irreversible metabolite-intermediate complexes. Finally, utilizing cyanide trapping and highresolution mass spectrometry, we illuminated the direct and sequential oxidative bioactivation of PEM and its major O-desmethylated metabolite at its distal morpholine moiety to reactive iminium ion hard electrophilic species that could covalently mechanism-based inactivate CYP3A.

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Molecular Dynamics Simulation Framework to Probe the Binding Hypothesis of CYP3A4 Inhibitors

Cited by 20 publications

References 106 publications

Single Nucleotide Polymorphism Induces Divergent Dynamic Patterns in CYP3A5: A Microsecond Scale Biomolecular Simulation of Variants Identified in Sub-Saharan African Populations

Single Nucleotide Polymorphism Induces Divergent Dynamic Patterns in CYP3A5: A Microsecond Scale Biomolecular Simulation of Variants Identified in Sub-Saharan African Populations

Computational Determination of Potential Multiprotein Targeting Natural Compounds for Rational Drug Design Against SARS-COV-2

Direct and Sequential Bioactivation of Pemigatinib to Reactive Iminium Ion Intermediates Culminates in Mechanism-Based Inactivation of Cytochrome P450 3A

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