An Integrated Systems Biology and Network-Based Approaches to Identify Novel Biomarkers in Breast Cancer Cell Lines Using Gene Expression Data

Khan, Abbas; Rehman, Zainab; Hashmi, Huma Farooque; Khan, Abdul Aziz; Junaid, Muhammad; Sayaf, Abrar Mohammad; Ali, Syed Shujait; Hassan, Fakhrul; Wang, Heng; Wei, Dong‐Qing

doi:10.1007/s12539-020-00360-0

Cited by 39 publications

(30 citation statements)

References 40 publications

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“…In this regard, in silico techniques such as MD simulations were utilized to study the said mutations role in PZase resistance to PZA. These methods are widely used to understand the mechanism of resistance and any binding perturbation caused by mutations ( Khan et al, 2020c , e , 2021a , b ). It unveils conformational changes of proteins caused by any intrinsic mutations or ligand binding.…”

Section: Discussionmentioning

confidence: 99%

Insights Into Mutations Induced Conformational Changes and Rearrangement of Fe2+ Ion in pncA Gene of Mycobacterium tuberculosis to Decipher the Mechanism of Resistance to Pyrazinamide

Nangraj

Khan

Umbreen

et al. 2021

Front. Mol. Biosci.

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Pyrazinamide (PZA) is the first-line drug commonly used in treating Mycobacterium tuberculosis (Mtb) infections and reduces treatment time by 33%. This prodrug is activated and converted to an active form, Pyrazinoic acid (POA), by Pyrazinamidase (PZase) enzyme. Mtb resistance to PZA is the outcome of mutations frequently reported in pncA, rpsA, and panD genes. Among the mentioned genes, pncA mutations contribute to 72–99% of the total resistance to PZA. Thus, considering the vital importance of this gene in PZA resistance, its frequent mutations (D49N, Y64S, W68G, and F94A) were investigated through in-depth computational techniques to put conclusions that might be useful for new scaffolds design or structure optimization to improve the efficacy of the available drugs. Mutants and wild type PZase were used in extensive and long-run molecular dynamics simulations in triplicate to disclose the resistance mechanism induced by the above-mentioned point mutations. Our analysis suggests that these mutations alter the internal dynamics of PZase and hinder the correct orientation of PZA to the enzyme. Consequently, the PZA has a low binding energy score with the mutants compared with the wild type PZase. These mutations were also reported to affect the binding of Fe2+ ion and its coordinated residues. Conformational dynamics also revealed that β-strand two is flipped, which is significant in Fe2+ binding. MM-GBSA analysis confirmed that these mutations significantly decreased the binding of PZA. In conclusion, these mutations cause conformation alterations and deformities that lead to PZA resistance.

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Section: Discussionmentioning

confidence: 99%

Insights Into Mutations Induced Conformational Changes and Rearrangement of Fe2+ Ion in pncA Gene of Mycobacterium tuberculosis to Decipher the Mechanism of Resistance to Pyrazinamide

Nangraj

Khan

Umbreen

et al. 2021

Front. Mol. Biosci.

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“…To connect the alanine mutations with the binding affinity changes, the binding free energy of each alanine substituted complex was determined. The free energy scoring function (MMGBSA) is an extensively used approach to evaluate the free energy of a protein-ligand, protein-protein and protein-nucleic acids ( Khan et al, 2018 ; Ali et al, 2019 ; Khan et al, 2019 ; Khan et al, 2020a ; Khan et al, 2020b ; Khan et al, 2020c ; Khan et al, 2020d ; Khan et al, 2020e ; Khan et al, 2020f ; Hussain et al, 2020 ). It used the following equation to calculate the free energy.…”

Section: Methodsmentioning

confidence: 99%

Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein–Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis

Hashmi

Waseem

Ali

et al. 2021

Front. Mol. Biosci.

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Epstein-Barr Virus (EBV) is considered the most important human pathogen due to its role in infections and cellular malignancies. It has been reported that this Oncolytic virus infects 90% world’s population. EBNA1 is required for DNA binding and survival of the virus and is considered an essential drug target. The biochemical and structural properties of this protein are known, but it is still unclear which residues impart a critical role in the recognition of dsDNA. Intending to disclose only the essential residues in recognition of dsDNA, this study used a computational pipeline to generate an alanine mutant of each interacting residue and determine the impact on the binding. Our analysis revealed that R469A, K514A, Y518A, R521A and R522A are the key hotspots for the recognition of dsDNA by the EBNA1. The dynamics properties, i.e. stability, flexibility, structural compactness, hydrogen bonding frequency, binding affinity, are altered by disrupting the protein-DNA contacts, thereby decreases the binding affinity. In particular, the two arginine substitution, R521A and R522A, significantly affected the total binding energy. Thus, we hypothesize that these residues impart a critical role in the dsDNA recognition and pathogenesis. This study would help to design structure-based drugs against the EBV infections.

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“…Key genes and pathways involved in different cancers and diseases have been identified by analyzing these data. These key genes can be used as biomarkers and can be utilized for early diagnosis, survival prediction, drug target identification, and drug response observation [5][6][7][8][9][10][11]. Bioinformatics analyses have been employed to identify important genes and pathways involved in the disease process of malignant pleural mesothelioma [12][13][14].…”

Section: Original Articlementioning

confidence: 99%

A network-biology approach for identification of key genes and pathways involved in malignant peritoneal mesothelioma

2021

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An Integrated Systems Biology and Network-Based Approaches to Identify Novel Biomarkers in Breast Cancer Cell Lines Using Gene Expression Data

Cited by 39 publications

References 40 publications

Insights Into Mutations Induced Conformational Changes and Rearrangement of Fe2+ Ion in pncA Gene of Mycobacterium tuberculosis to Decipher the Mechanism of Resistance to Pyrazinamide

Insights Into Mutations Induced Conformational Changes and Rearrangement of Fe2+ Ion in pncA Gene of Mycobacterium tuberculosis to Decipher the Mechanism of Resistance to Pyrazinamide

Structural and Biophysical Investigation of the Key Hotspots on the Surface of Epstein–Barr Nuclear Antigen 1 Essential for DNA Recognition and Pathogenesis

A network-biology approach for identification of key genes and pathways involved in malignant peritoneal mesothelioma

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