Mechanistic insights on nsSNPs on binding site of renin and cytochrome P450 proteins: A computational perceptual study for pharmacogenomics evaluation

Loganathan, Lakshmanan; Kuriakose, Beena Briget; Mushfiq, Sakeena; Muthusamy, Karthikeyan

doi:10.1002/jcb.30069

Cited by 15 publications

(7 citation statements)

References 44 publications

(39 reference statements)

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“…Recent reports on amino acid substitutions such as S135C, P208S, and G340V are essential in the establishment of interaction in hypertension (Loganathan et al, 2021). Currently, the molecular and pathogenesis paradigm of hypertension has not been yet fully explained.…”

Section: Resultsmentioning

confidence: 99%

Structural and dynamic investigation of non‐synonymous variations in Renin–AGT complex revealed altered binding via hydrogen‐bonding network reprogramming to accelerate the hypertension pathway

et al. 2022

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Hypertension is one of the major issues worldwide and one of the main factors involved in heart and kidney failure. Angiotensinogen and renin are key components of the renin-angiotensin-aldosterone system, which plays an indispensable role in hypertension. The aim of this study was to find out the nonsynonymous mutations and structure-based mutation-function correlation in the renin-AGT complex and reveal the most deleterious mutations to accelerated hypertension. In the current study, we employed computational modeling and molecular simulation approaches to demonstrate the impact of specific mutations in the REN-AGT interface in hypertension. Computational algorithms, that is, PhD-SNP, PolyPhen-1, MAPP, Sorting Intolerant from Tolerant, Screening of non-acceptable polymorphism, PredictSNP, PolyPhen-2, and Protein Analysis Through Evolutionary Relationships predicted 20 mutations as deleterious in AGT while only five mutations were confirmed as deleterious in the renin protein. Investigation of the bonding analysis revealed that two mutations S107L and V193F in renin altered the hydrogen-bonding paradigm at the interface site.Furthermore, exploration of structural-dynamic behaviors demonstrated by that these mutations also increases the structural stability to regulate the expression of disease pathway. The flexibility index of each residues and structural compactness analysis further validated the findings by portraying the difference in the dynamic behavior in contrast to the wild type. Binding energy calculations based on molecular mechanics/generalized Born surface area methods were used which further established the binding differences between the wild type, S107L, and V193F mutant variants. The total binding energy for wild type, S107L, and V193F was reported to be −27. 79, −47.72, and −38.25, respectively. In conclusion, these two mutations increase the binding free energy alongside the docking score to enhance the binding between renin and AGT to overexpress this pathway in a | 731 AHMAD et al.

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Section: Resultsmentioning

confidence: 99%

Structural and dynamic investigation of non‐synonymous variations in Renin–AGT complex revealed altered binding via hydrogen‐bonding network reprogramming to accelerate the hypertension pathway

et al. 2022

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“…Using bioinformatics tools and algorithms helps us quickly design and execute an analysis without laborious and time-consuming experimental work [30]. This type of analysis of nsSNPs is substantiating to refine the molecular characterization of nsSNPs that would contribute massive support in personalized medication development [31].…”

Section: Discussionmentioning

confidence: 99%

Molecular Modelling of nsSNPs in GABRA2 Gene In Epilepsy And Study Of Their Impact On Structure And Stability of GABRA2 Protein

2022

JGEBR

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Epilepsy is a neurological condition characterized by abrupt, unprovoked, and recurrent seizures that are unpredictable in frequency. The objective of this analysis was to identify novel nonsynonymous polymorphisms in the GABRA2 gene and determine their effect on protein structure and stability. Most pathogenic/deleterious nsSNPs were predicted using six different bioinformatic tools. Mutpred2, Mupro was used to check the impact of identified nsSNPS on protein structure and stability. The pathogenic score of SNPs was predicted using the FATHMM tool. The CONSURF webserver was used for conservation analysis of pathogenic SNPs.3-D structure of the protein was realized using SWISS-MODEL and residue position in protein visualized by Lite Mol. GeneMANIA and STRING database is used to predict the function of interlinked gene interactions. Out of 228 nsSNPs retrieved from the dbSNP database, we identified a novel missense variant, F285S (rs41310789) as most deleterious and its possible association with epilepsy syndrome focal epilepsy. Stability and conservation analysis results interpret rs41310789 present in evolutionarily conserved regions of a gene and affect its structure. This analysis provides information regarding the impact of nsSNPs that might affect the structure and activity of GABRA2 protein. Thus, these coding variants should be taken into scrutiny while genetic screening of epileptic patients.

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“…Using bioinformatics tools and algorithms helps us quickly design and execute an analysis without laborious and time-consuming experimental work (Khatun et al, 2020). This type of analysis of nsSNPs is substantiating to re ne the molecular characterization of nsSNPs that would contribute massive support in personalized medication development (Loganathan et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Molecular Modelling of nsSNPs in GABRA2 Gene in Epilepsy and Study of Their Impact On Structure and Stability of GABRA2 Protein

Agha

Azam

Faryal

2021

Preprint

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Epilepsy is a neurological condition characterized by abrupt, unprovoked, and recurrent seizures that are unpredictable in frequency. The objective of this analysis was to identify novel non-synonymous polymorphisms in the GABRA2 gene and determine their effect on protein structure and stability. Most pathogenic/deleterious nsSNPs were predicted using six different bioinformatic tools. Mutpred2, Mupro was used to check the impact of identified nsSNPS on protein structure and stability. The pathogenic score of SNPs was predicted using the FATHMM tool. The CONSURF webserver was used for conservation analysis of pathogenic SNPs.3-D structure of the protein was realized using SWISS-MODEL and residue position in protein visualized by Lite Mol. GeneMANIA and STRING databases were used to predict the function of interlinked gene interactions. Out of 228 nsSNPs retrieved from the dbSNP database, we identified a novel missense variant, F285S (rs41310789), as most deleterious and its possible association with epilepsy syndrome focal epilepsy. Stability and conservation analysis results interpret rs41310789 present in evolutionarily conserved regions of a gene and affect its structure. This analysis provides information regarding the impact of nsSNPs that might affect the structure and activity of GABRA2 protein. Thus, these coding variants should be taken into scrutiny while genetic screening of epileptic patients.

show abstract

Mechanistic insights on nsSNPs on binding site of renin and cytochrome P450 proteins: A computational perceptual study for pharmacogenomics evaluation

Cited by 15 publications

References 44 publications

Structural and dynamic investigation of non‐synonymous variations in Renin–AGT complex revealed altered binding via hydrogen‐bonding network reprogramming to accelerate the hypertension pathway

Structural and dynamic investigation of non‐synonymous variations in Renin–AGT complex revealed altered binding via hydrogen‐bonding network reprogramming to accelerate the hypertension pathway

Molecular Modelling of nsSNPs in GABRA2 Gene In Epilepsy And Study Of Their Impact On Structure And Stability of GABRA2 Protein

Molecular Modelling of nsSNPs in GABRA2 Gene in Epilepsy and Study of Their Impact On Structure and Stability of GABRA2 Protein

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