Computational Screening and Analysis of Lung Cancer Related Non-Synonymous Single Nucleotide Polymorphisms on the Human Kirsten Rat Sarcoma Gene

Wang, Qiankun; Mehmood, Aamir; Wang, Heng; Xu, Qin; Xiong, Yi; Wei, Dong‐Qing

doi:10.3390/molecules24101951

Cited by 32 publications

(25 citation statements)

References 38 publications

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“…SASA is a measure of the exposed surface in protein structures that can be accessible to solvent molecules [ 55 ]. SASA analysis thus provides relevant information into the protein’s degree of exposure to its environment over time [ 56 ]. The SASA values computed throughout the simulations ( Fig 11 ) pointed to an unstable behavior at the beginning of all simulations.…”

Section: Resultsmentioning

confidence: 99%

Comprehensive in silico analysis and molecular dynamics of the superoxide dismutase 1 (SOD1) variants related to amyotrophic lateral sclerosis

2021

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Amyotrophic Lateral Sclerosis (ALS) is the most frequent motor neuron disorder, with a significant social and economic burden. ALS remains incurable, and the only drugs approved for its treatments confers a survival benefit of a few months for the patients. Missense mutations in superoxide dismutase 1 (SOD1), a major cytoplasmic antioxidant enzyme, has been associated with ALS development, accounting for 23% of its familial cases and 7% of all sporadic cases. This work aims to characterize in silico the structural and functional effects of SOD1 protein variants. Missense mutations in SOD1 were compiled from the literature and databases. Twelve algorithms were used to predict the functional and stability effects of these mutations. ConSurf was used to estimate the evolutionary conservation of SOD1 amino-acids. GROMACS was used to perform molecular dynamics (MD) simulations of SOD1 wild-type and variants A4V, D90A, H46R, and I113T, which account for approximately half of all ALS-SOD1 cases in the United States, Europe, Japan, and United Kingdom, respectively. 233 missense mutations in SOD1 protein were compiled from the databases and literature consulted. The predictive analyses pointed to an elevated rate of deleterious and destabilizing predictions for the analyzed variants, indicating their harmful effects. The ConSurf analysis suggested that mutations in SOD1 mainly affect conserved and possibly functionally essential amino acids. The MD analyses pointed to flexibility and essential dynamics alterations at the electrostatic and metal-binding loops of variants A4V, D90A, H46R, and I113T that could lead to aberrant interactions triggering toxic protein aggregation. These alterations may have harmful implications for SOD1 and explain their association with ALS. Understanding the effects of SOD1 mutations on protein structure and function facilitates the design of further experiments and provides relevant information on the molecular mechanism of pathology, which may contribute to improvements in existing treatments for ALS.

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Section: Resultsmentioning

confidence: 99%

Comprehensive in silico analysis and molecular dynamics of the superoxide dismutase 1 (SOD1) variants related to amyotrophic lateral sclerosis

2021

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“…The rarity of these alterations in the normal population suggests some pathogenic role for the tumor (Li et al., 2017), although in silico predictive scores describe only some of them as pathogenic. In particular, two of them (i.e, KRAS A130V and PPM1D K469E) have been described as non-pathogenic/neutral alterations (Ruark et al., 2013, Wang et al., 2019). Even less is known about the new somatic indel mutation (i.e., RET c.1894_1902delGAGCTGTGC; p.E632_C634del) that has never been described previously (Table 2).…”

Section: Discussionmentioning

confidence: 99%

Genetic Landscape of Somatic Mutations in a Large Cohort of Sporadic Medullary Thyroid Carcinomas Studied by Next-Generation Targeted Sequencing

et al. 2019

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SummarySporadic Medullary Thyroid Carcinoma (sMTC) is a rare but aggressive thyroid tumor. RET and RAS genes are present in about 50%–80% of cases, but most of the remaining cases are still orphan of a genetic driver. We studied the largest series of sMTC by deep sequencing to define the mutational landscape. With this methodology we greatly reduced the number of RET- or RAS-negative cases and we confirmed the central role of RET and RAS mutations. Moreover, we highlighted the bad prognostic role of RET mutations in sMTC and consolidated the favorable prognostic role of RAS mutations. For the first time, we showed that the variant allele frequency represents an additional prognostic marker inside the group of RET-mutated sMTC.

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“…In the present work, we employed MD simulation to examine the stability of our shortlisted compounds in the active site of the Mpro at different time intervals. Hence, the shortlisted compounds individually in a complex with the Mpro were subjected to MD simulation via GROMACS v.5.1 [ 27 ] . The All-atom OPLS force field [ 28 ] was employed in this case.…”

Section: Methodsmentioning

confidence: 99%

Discovering potent inhibitors against the Mpro of the SARS-CoV-2. A medicinal chemistry approach

Mehmood¹,

Nawab²,

Wang³

et al. 2022

Computers in Biology and Medicine

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The global pandemic caused by a single-stranded RNA (ssRNA) virus known as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still at its peak, with new cases being reported daily. Although the vaccines have been administered on a massive scale, the frequent mutations in the viral gene and resilience of the future strains could be more problematic. Therefore, new compounds are always needed to be available for therapeutic approaches. We carried out the present study to discover potential drug compounds against the SARS-CoV-2 main protease (Mpro). A total of 16,000 drug-like small molecules from the ChemBridge database were virtually screened to obtain the top hits. As a result, 1032 hits were selected based on their docking scores. Next, these structures were prepared for molecular docking, and each small molecule was docked into the active site of the Mpro. Only compounds with solid interactions with the active site residues and the highest docking score were subjected to molecular dynamics (MD) simulation. The post-simulation analyses were carried out using the in-built GROMACS tools to gauge the stability, flexibility, and compactness. Principal component analysis (PCA) and hydrogen bonding were also calculated to observe trends and affinity of the drugs towards the target. Among the five top compounds, C1, C3, and C6 revealed strong interaction with the target's active site and remained highly stable throughout the simulation. We believe the predicted compounds in this study could be potential inhibitors in the natural system and can be utilized in designing therapeutic strategies against the SARS-CoV-2.

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Computational Screening and Analysis of Lung Cancer Related Non-Synonymous Single Nucleotide Polymorphisms on the Human Kirsten Rat Sarcoma Gene

Cited by 32 publications

References 38 publications

Comprehensive in silico analysis and molecular dynamics of the superoxide dismutase 1 (SOD1) variants related to amyotrophic lateral sclerosis

Comprehensive in silico analysis and molecular dynamics of the superoxide dismutase 1 (SOD1) variants related to amyotrophic lateral sclerosis

Genetic Landscape of Somatic Mutations in a Large Cohort of Sporadic Medullary Thyroid Carcinomas Studied by Next-Generation Targeted Sequencing

Discovering potent inhibitors against the Mpro of the SARS-CoV-2. A medicinal chemistry approach

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