In-silico screening and analysis of missense SNPs in human CYP3A4/5 affecting drug-enzyme interactions of FDA-approved COVID-19 antiviral drugs.

In-silico screening and analysis of missense SNPs in human CYP3A4/5 affecting drug-enzyme interactions of FDA-approved COVID-19 antiviral drugs.

Publication date: Jan 16, 2025

Single nucleotide polymorphisms (SNPs) represent the prevailing form of genetic variations observed in the human population. Such variations could alter the encoded enzymes’ activities. CYP3A4/5 enzymes are involved in metabolizing drugs, notably antivirals against SARS-CoV-2. In this work, we computationally investigated antiviral-enzyme interactions of CYP3A4/5 genetic variants. We also examined the deleterious impact of 751 missense single nucleotide polymorphisms (SNPs) within the CYP3A4/5 genes. An ensemble of bioinformatics tools, [SIFT, PolyPhen-2, cadd, revel, metaLr, mutation assessor, Panther, SNP&GO, PhD-SNP, SNAP, Meta-SNP, FATHMM, I-Mutant, MuPro, INPS, CONSURF, GPS 5. 0, MusiteDeep and NetPhos], identified a total of 94 variants (47 SNPs in CYP3A4, 47 SNPs in CYP3A5) to potentially impact the structural integrity as well as the activity of the CYP3A4/5 enzymes. Molecular docking was done to recognize the structural stability and binding properties of the CYP3A4/5 protein isoforms with 3 FDA-approved antiviral drugs. Our findings indicated that the CYP3A4 gene variants; R418T, I335T and R130P and the CYP3A5 gene variants; I335T, L133P and R130Q are considered the most deleterious missense SNPs. These mutants potentially affect drug-enzyme binding and hence may alter therapeutic response. Cataloguing deleterious SNPs is essential for personalized gene-based pharmacotherapy.

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Concepts Keywords
Antivirals Antiviral Agents
Cyp3a5 Antiviral Agents
Gps Computational Biology
Mutants Computer Simulation
Pharmacotherapy COVID-19
COVID-19 Drug Treatment
Humans
Molecular Docking Simulation
Mutation, Missense
Polymorphism, Single Nucleotide
SARS-CoV-2

Semantics

Type Source Name
disease MESH COVID-19
disease IDO protein
drug DRUGBANK Ritonavir
pathway REACTOME Translation
drug DRUGBANK Coenzyme M
pathway REACTOME Metabolism
disease MESH emergency
disease IDO susceptibility
disease MESH drug interactions
disease IDO homo sapiens
drug DRUGBANK Isoxaflutole
disease IDO macromolecule
drug DRUGBANK Serine
drug DRUGBANK L-Threonine
drug DRUGBANK L-Tyrosine
disease IDO site
drug DRUGBANK ANX-510
drug DRUGBANK Huperzine B
disease IDO algorithm
disease IDO quality
drug DRUGBANK Water
disease IDO process
disease MESH clinical significance
drug DRUGBANK Amino acids
disease MESH anomalies
drug DRUGBANK Pentaerythritol tetranitrate
drug DRUGBANK L-Arginine
drug DRUGBANK Glutamic Acid
drug DRUGBANK L-Lysine
drug DRUGBANK L-Isoleucine
drug DRUGBANK L-Glutamine
drug DRUGBANK L-Leucine
drug DRUGBANK Proline
drug DRUGBANK L-Asparagine
drug DRUGBANK Methionine
drug DRUGBANK L-Valine
drug DRUGBANK L-Phenylalanine
disease MESH chronic diseases
disease MESH point mutations
disease MESH Ebola virus infection
pathway KEGG Drug metabolism
disease MESH treatment failures
disease MESH infection
drug DRUGBANK Chloroquine
drug DRUGBANK Hydroxychloroquine
disease MESH relapse
disease MESH genetic diseases
disease MESH tyrosinemia
disease MESH Hawkinsinuria
drug DRUGBANK Lidocaine
drug DRUGBANK Diethylstilbestrol
drug DRUGBANK Iron
pathway REACTOME Reproduction

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