Dynamics Insights Into the Gain of Flexibility by Helix-12 in ESR1 as a Mechanism of Resistance to Drugs in Breast Cancer Cell Lines

Khan, Abbas; Ashfaq-Ur-Rehman,; Junaid, Muhammad; Li, Chengdong; Saleem, Shoaib; Humayun, Fahad; Shamas, Shazia; Ali, Syed Shujait; Babar, Zainib; Wei, Dong‐Qing

doi:10.3389/fmolb.2019.00159

Cited by 40 publications

(24 citation statements)

References 62 publications

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“…The position, binding, structure integrity and association of the zinc metals in the protein structure is also sketched. Computational methods are of great importance in determining the structure and function of proteins, drug binding, exploring the resistance mechanism and biocatalysis[28][29][30].Our analysis is in accordance with the previously reported SARS-CoV identical protein, where the nsp12 protein interacts with the CoV RNA, and the required stability is provided with the nsps, including nsp7 and nsp8. Further, the nsp12 is also involved in template recognition.…”

supporting

confidence: 88%

Decoding the structure of RNA-dependent RNA-polymerase (RdRp), understanding the ancestral relationship and dispersion pattern of 2019 Wuhan Coronavirus

Khan¹,

Khan²,

Saleem³

et al. 2020

Preprint

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Most recently, an outbreak of severe pneumonia caused by the infection of 2019-nCoV, a novel coronavirus first identified in Wuhan, China, imposes serious threats to public health. Upon infecting host cells, coronaviruses assemble a multi-subunit RNA-synthesis complex of viral non-structural proteins (nsp) responsible for the replication and transcription of the viral genome. Therefore, the role and inhibition of nsp12 are indispensable. Since there is no crystallographic structure of RdRp is available, so, here, we present the 3-dimensional structure of the 2019-nCoV nsp12 polymerase using a computational approach. nsp12 of 2019-nCoV possesses an architecture common to all viral polymerases as well as a large N-terminal extension. This structure illuminates the assembly of the coronavirus core RNA-synthesis machinery, provides key insights into nsp12 polymerase catalysis and fidelity, and acts as a template for the design of novel antiviral therapeutics. Besides, the experimental structure could reveal the organization in a more sophisticated way. Furthermore, the ancestral state reconstruction suggests the possible evolution of nCoV in Wuhan China and its dispersal to the USA. The result of our analyses postulates the possible dispersal of nCoV from the USA and Shenzhen back to Wuhan. This disclosing of valuable knowledge regarding the 3D structure of 2019-nCoV nsp12 architecture, ancestral relation, and dispersion pattern could help to design effective therapeutic candidates against the coronaviruses and design robust preventive measurements.

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supporting

confidence: 88%

Decoding the structure of RNA-dependent RNA-polymerase (RdRp), understanding the ancestral relationship and dispersion pattern of 2019 Wuhan Coronavirus

Khan¹,

Khan²,

Saleem³

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Computational methods are of great importance in determining the structure and function of proteins, drug binding, exploring the resistance mechanism, and bio-catalysis [41][42][43]. So, herein, using structure-based virtual screening approach shortlisted the top hits which forms important hydrogen, hydrophobic and other important interactions with the RdRp active site residues.…”

Section: Discussionmentioning

confidence: 99%

“…The binding of each ligand was estimated by using the molecular mechanics Poisson-Boltzmann surface area (MMGBSA) method which is a widely used and acceptable method [36][37][38][39][40]. The most widely used MMPBSA.py script was used as input, which contain all the guidelines for free energy calculations.…”

Section: Binding Free Energy Calculationsmentioning

confidence: 99%

Phylogenetic Analysis and Structural Perspectives of RNA-Dependent RNA-Polymerase Inhibition from SARs-CoV-2 with Natural Products

Khan

Saleem

et al. 2020

Interdiscip Sci Comput Life Sci

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Most recently, an outbreak of severe pneumonia caused by the infection of SARS-CoV-2, a novel coronavirus first identified in Wuhan, China, imposes serious threats to public health. Upon infecting host cells, coronaviruses assemble a multi-subunit RNA-synthesis complex of viral non-structural proteins (nsp) responsible for the replication and transcription of the viral genome. Therefore, the role and inhibition of nsp12 are indispensable. A cryo-EM structure of RdRp from SARs-CoV-2 was used to identify novel drugs from Northern South African medicinal compounds database (NANPDB) by using computational virtual screening and molecular docking approaches. Considering Remdesivir as the control, 42 compounds were shortlisted to have docking score better than Remdesivir. The top 5 hits were validated by using molecular dynamics simulation approach and free energy calculations possess strong inhibitory properties than the Remdesivir. Thus, this study paved a way for designing novel drugs by decoding the architecture of an important enzyme and its inhibition with compounds from natural resources. This disclosing of necessary knowledge regarding the screening and the identification of top hits could help to design effective therapeutic candidates against the coronaviruses and design robust preventive measurements.

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“…Finally, several other mutations have also been identified more recently [536,537,540,541]. An E380Q mutation found in helix 12 next to the estrogen binding site increases the flexibility of this helix and decreases the affinity of the protein for the drug [542]. Not discussed here are resistant mutations in aromatase (CYP19A1).…”

Section: Classificationmentioning

confidence: 96%

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

Hamid

Petreaca

2020

Cancers

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Secondary resistant mutations in cancer cells arise in response to certain small molecule inhibitors. These mutations inevitably cause recurrence and often progression to a more aggressive form. Resistant mutations may manifest in various forms. For example, some mutations decrease or abrogate the affinity of the drug for the protein. Others restore the function of the enzyme even in the presence of the inhibitor. In some cases, resistance is acquired through activation of a parallel pathway which bypasses the function of the drug targeted pathway. The Catalogue of Somatic Mutations in Cancer (COSMIC) produced a compendium of resistant mutations to small molecule inhibitors reported in the literature. Here, we build on these data and provide a comprehensive review of resistant mutations in cancers. We also discuss mechanistic parallels of resistance.

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Dynamics Insights Into the Gain of Flexibility by Helix-12 in ESR1 as a Mechanism of Resistance to Drugs in Breast Cancer Cell Lines

Cited by 40 publications

References 62 publications

Decoding the structure of RNA-dependent RNA-polymerase (RdRp), understanding the ancestral relationship and dispersion pattern of 2019 Wuhan Coronavirus

Decoding the structure of RNA-dependent RNA-polymerase (RdRp), understanding the ancestral relationship and dispersion pattern of 2019 Wuhan Coronavirus

Phylogenetic Analysis and Structural Perspectives of RNA-Dependent RNA-Polymerase Inhibition from SARs-CoV-2 with Natural Products

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

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