VERMA Chandra

Role of the N-terminal lid in regulating the interaction of phosphorylated MDMX with p53

Murine double minute 4 protein (MDMX) is crucial for the regulation of the tumor suppressor protein p53. Phosphorylation of the N-terminal domain of MDMX is thought to affect its binding with the transactivation domain of p53, thus playing a role in p53 regulation. In this study, the effects of MDMX phosphorylation on the binding of p53 were investigated using molecular dynamics simulations.

type: 
Journal Paper
journal: 
Oncotarget, 2017, Vol. 8, No. 68, Pg 112825-112840, doi.org/10.18632/oncotarget.22829
Url: 
http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=22829
Impact Factor: 
5.168
Date of acceptance: 
2017-10-05

Modeling the full length HIV-1 Gag polyprotein reveals the role of its p6 subunit in viral maturation and the effect of non-cleavage site mutations in protease drug resistance

HIV polyprotein Gag is increasingly found to contribute to protease inhibitor resistance. Despite its role in viral maturation and in developing drug resistance, there remain gaps in the knowledge of the role of certain Gag subunits (e.g. p6), and that of non-cleavage mutations in drug resistance. As p6 is flexible, it poses a problem for structural experiments, and is hence often omitted in experimental Gag structural studies.

type: 
Journal Paper
journal: 
Journal of Biomolecular Structure and Dynamics, 2017, Pg 1-40, doi: 10.1080/07391102.2017.1417160
pubmed: 
3.123
Url: 
http://www.tandfonline.com/doi/abs/10.1080/07391102.2017.1417160
Date of acceptance: 
2017-12-05

Structural analysis of protein tyrosine phosphatase 1B reveals potentially druggable allosteric binding sites

Catalytic proteins such as human protein tyrosine phosphatase 1B (PTP1B), with conserved and highly polar active sites, warrant the discovery of druggable non-active sites, such as allosteric sites, and potentially, therapeutic small molecules that can bind to these sites. Catalyzing the dephosphorylation of numerous substrates, PTP1B is physiologically important in intracellular signal transduction pathways in diverse cell types and tissues. Aberrant PTP1B is associated with obesity, diabetes, cancers, and neurodegenerative disorders.

type: 
Journal Paper
journal: 
Proteins: Structure, Function, and Bioinformatics, 13 Dec 2017, doi: 10.1002/prot.25440
pubmed: 
29235148
Url: 
https://www.ncbi.nlm.nih.gov/pubmed/29235148
Impact Factor: 
2.499
Date of acceptance: 
2017-12-27

An Intramolecular Tryptophan-Condensation Approach for Peptide Stapling

Stapled peptides are gaining tremendous interest as next-generation therapeutic agents to target protein-protein interactions. Herein, we report an intramolecular peptide stapling method which links two tryptophan residues at C2 position of the indole moieties via acid-mediated condensation with an aldehyde.

type: 
Journal Paper
journal: 
Organic & Biomolecular Chemistry, 2017, doi: 10.1039/C7OB02667F
Url: 
http://pubs.rsc.org/en/content/articlelanding/2017/ob/c7ob02667f#!divAbstract
Impact Factor: 
3.564
Date of acceptance: 
2017-12-07

Characterizing the Conformational Landscape of MDM2-binding p53 peptides using Molecular Dynamics simulations

The conformational landscapes of p53 peptide variants and phage derived peptide (12/1) variants, all known to bind to MDM2, are studied using hamiltonian replica exchange molecular dynamics simulations. Complementing earlier observations, the current study suggests that the p53 peptides largely follow the ‘conformational selection’ paradigm in their recognition of and complexation by MDM2 while the 12/1 peptides likely undergo some element of conformational selection but are mostly driven by ‘binding induced folding’.

type: 
Journal Paper
journal: 
Scientific Reports 7, Article no:15600, 2017, doi:10.1038/s41598-017-15930-4
Url: 
https://www.nature.com/articles/s41598-017-15930-4
Impact Factor: 
4.259
Date of acceptance: 
2017-11-03

Small molecules targeting the inactive form of the Mnk 1/2 kinases

Overexpression of the eukaryotic initiation factor 4E (eIF4E) is linked to a variety of cancers. Both mitogenactivated protein kinases-interacting kinases 1 and 2 (Mnk1/2) activate the oncogene eIF4E through posttranslational modification (phosphorylating it at the conserved Ser209). Inhibition of Mnk prevents eIF4E phosphorylation, making the Mnk−eIF4E axis a potential therapeutic target for oncology. Recently, the design and synthesis of a series of novel potent compounds inhibiting the Mnk1/2 kinases were carried out in-house.

type: 
Journal Paper
journal: 
ACS Omega 2017, 2, Pg 7881 - 7891, doi: 10.1021/acsomega.7b01403
Date of acceptance: 
2017-10-31

A yeast two-hybrid system for the screening and characterization of small-molecule inhibitors of protein–protein interactions identifies a novel putative Mdm2-binding site in p53

Background: Protein–protein interactions (PPIs) are fundamental to the growth and survival of cells and serve as excellent targets to develop inhibitors of biological processes such as host-pathogen interactions and cancer cell proliferation. However, isolation of PPI inhibitors is extremely challenging. While several in vitro assays to screen for PPI inhibitors are available, they are often expensive, cumbersome, and require large amounts of purified protein. In contrast, limited in vivo assays are available to screen for small-molecule inhibitors of PPI.

type: 
Journal Paper
journal: 
BMC Biology 2017 15:108, doi: 10.1186/s12915-017-0446-7
Url: 
https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-017-0446-7
Impact Factor: 
6.779
Date of acceptance: 
2017-10-19

A New Generation of Arachidonic Acid Analogues as Potential Neurological Agent Targeting Cytosolic Phospholipase A2

Cytosolic phospholipase A2 (cPLA2) is an enzyme that releases arachidonic acid (AA) for the synthesis of eicosanoids and lysophospholipids which play critical roles in the initiation and modulation of oxidative stress and neuroinflammation. In the central nervous system, cPLA2 activation is implicated in the pathogenesis of various neurodegenerative diseases that involves neuroinflammation, thus making it an important pharmacological target. In this paper, a new class of arachidonic acid (AA) analogues was synthesized and evaluated for their ability to inhibit cPLA2.

type: 
Journal Paper
journal: 
Scientific Reports 7, Article no: 13684, 2017, doi:10.1038/s41598-017-13996-8
Url: 
https://www.nature.com/articles/s41598-017-13996-8
Impact Factor: 
4.259
Date of acceptance: 
2017-10-05

Editorial Overview : Exploring mechanisms in biology: simulations and experiments come together

type: 
Journal Paper
journal: 
Progress in Biophysics and Molecular Biology, 2017 Sep;128:1-2. doi: 10.1016/j.pbiomolbio.2017.07.005
pubmed: 
28743422
Impact Factor: 
3.227

The interfacial character of antibody paratopes: analysis of antibody-antigen structures

In this study, computational methods are applied to investigate the general properties of antigen engaging residues of a paratope from a non-redundant dataset of 403 antibody-antigen complexes to dissect the contribution of hydrogen bonds, hydrophobic, van der Waals contacts and ionic interactions, as well as role of water molecules in the antigen-antibody interface. Consistent with previous reports using smaller datasets, we found that Tyr, Trp, Ser, Asn, Asp, Thr, Arg, Gly, His contribute substantially to the interactions between antibody and antigen.

type: 
Journal Paper
journal: 
Bioinformatics, 2017, doi: 10.1093/bioinformatics/btx389
Url: 
https://academic.oup.com/bioinformatics/article-lookup/doi/10.1093/bioinformatics/btx389
Impact Factor: 
7.307
Date of acceptance: 
2017-06-11
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