KANNAN Srinivasaraghavan

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 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

The Multifaceted Roles of Molecular Dynamics Simulations in Drug Discovery

Discovery of new therapeutics is a very challenging, expensive and time-consuming process. With the number of approved drugs declining steadily, combined with increasing costs, a rational approach is needed to facilitate, expedite and streamline the drug discovery process. In silico methods are playing key roles in the discovery of a growing number of marketed drugs. The use of computational approaches, particularly molecular dynamics, in drug design is rapidly gaining momentum and acceptance as an essential part of the toolkit for modern drug discovery.

type: 
Journal Paper
journal: 
Current Pharmaceutical Design, Vol. 22, Issue 23, 2016, Pg. 3585-3600, doi: 10.2174/1381612822666160425120507
pubmed: 
27108593
Url: 
http://www.eurekaselect.com/141460/article#
Impact Factor: 
3.052
Date of acceptance: 
2016-04-22

PDK1-SGK1 signaling sustains AKT-independent mTORC1 activation and confers resistance to PI3Kα inhibition

PIK3CA, which encodes the p110α subunit of PI3K, is frequently mutated and oncogenic in breast cancer. PI3Kα inhibitors are in clinical development and despite promising early clinical activity, intrinsic resistance is frequent among patients. We have previously reported that residual downstream mTORC1 activity upon treatment with PI3Kα inhibitors drives resistance to these agents. However, the mechanism underlying this phenotype is not fully understood. Here we show that in cancer cells resistant to PI3Kα inhibition, PDK1 blockade restores sensitivity to these therapies.

type: 
Journal Paper
journal: 
Cancer Cell 2016 Aug 8;30(2):229-242. doi: 10.1016/j.ccell.2016.06.004
pubmed: 
27451907
Url: 
http://www.ncbi.nlm.nih.gov/pubmed/27451907
Impact Factor: 
12.02
Date of acceptance: 
2016-06-09

Long range recognition and selection in IDPs: the interactions of the C-terminus of p53

The C-terminal domain of p53 is an extensively studied IDP, interacting with different partners through multiple distinct conformations. To explore the interplay between preformed structural elements and intrinsic fluctuations in its folding and binding we combine extensive atomistic equilibrium and non-equilibrium simulations. We find that the free peptide segment rapidly interconverts between ordered and disordered states with significant populations of the conformations that are seen in the complexed states.

type: 
Journal Paper
journal: 
Scientific Reports 2016 Mar 31; 6:23750. doi: 10.1038/srep23750
pubmed: 
27030593
Url: 
http://www.nature.com/articles/srep23750
Impact Factor: 
5.228
Date of acceptance: 
2016-03-15

Wetting of non-conserved residue-backbones: A feature indicative of aggregation associated regions of proteins

Aggregation is an irreversible form of protein complexation and often toxic to cells. The process entails partial or major unfolding that is largely driven by hydration. We model the role of hydration in aggregation using ‘Dehydrons'. ‘Dehydrons' are unsatisfied backbone hydrogen bonds in proteins that seek shielding from water molecules by associating with ligands or proteins. We find that the residues at aggregation interfaces have hydrated backbones, and in contrast to other forms of protein-protein interactions, are under less evolutionary pressure to be conserved.

type: 
Journal Paper
journal: 
Proteins. 2015 Dec 17. doi: 10.1002/prot.24976
pubmed: 
, PMID: 26677132
Url: 
http://www.ncbi.nlm.nih.gov/pubmed/26677132
Impact Factor: 
2.627

AKT signaling in ERBB2-amplified breast cancer

The PI3K/AKT pathway is the focus of several targeted therapeutic agents for a variety of malignancies. In ERBB2-amplified breast cancer, the hyperactivation of this signaling cascade is associated with resistance to ERBB2-targeted therapy. This can occur through gain-of-function alterations or compensatory mechanisms that enter into play upon pharmacological pressure.

type: 
Journal Paper
journal: 
Pharmacology & Therapeutics, 2015, Dec 2, doi: 10.1016/j.pharmthera.2015.11.013
pubmed: 
26645663
Url: 
http://www.ncbi.nlm.nih.gov/pubmed/26645663
Impact Factor: 
9.723

Mussels adhesion is dictated by time-regulated secretion and molecular confirmation of mussel adhesive proteins

Interfacial water constitutes a formidable barrier to strong surface bonding, hampering the development of water-resistant synthetic adhesives. Notwithstanding this obstacle, the Asian green mussel Perna viridis attaches firmly to underwater surfaces via a proteinaceous secretion (byssus). Extending beyond the currently known design principles of mussel adhesion, here we elucidate the precise time-regulated secretion of P. viridis mussel adhesive proteins.

type: 
Journal Paper
journal: 
Nature Communications 6, No. 8737, 2015, doi:10.1038/ncomms9737
Url: 
http://www.nature.com/ncomms/2015/151028/ncomms9737/full/ncomms9737.html
Impact Factor: 
11.47
Date of acceptance: 
2015-09-24

Probing the Binding Mechanism of Mnk Inhibitors by Docking and Molecular Dynamics Simulations

Mitogen-activated protein kinases-interacting kinase 1 and 2 (Mnk1/2) activate the oncogene eukaryotic initiation factor 4E (eIF4E) by phosphorylation. High level of phosphorylated eIF4E is associated with various types of cancers. Inhibition of Mnk prevents eIF4E phosphorylation, making them potential therapeutic targets for cancer. Recently, we have designed and synthesized a series of novel imidazopyridine and imidazopyrazine derivatives that inhibit Mnk1/2 kinases with potency in the nanomolar to micromolar range.

type: 
Journal Paper
journal: 
Biochemistry 2014
pubmed: 
25431995
Url: 
http://www.ncbi.nlm.nih.gov/pubmed/25431995

mAb806 binding to EGFR: a computational study

The epidermal growth factor receptor (EGFR) is an important target in the treatment of cancer. A very potent antibody, mAb806, has been developed against overexpressed EGFR and was found to be particularly active in brain tumours. Structural studies reveal that it binds an epitope on the extracellular region of the EGFR. However, this epitope is cryptic / buried in crystal structures of the active (untethered) and inactive (tethered) EGFR and it is unclear as to how the antibody interacts with this region.

type: 
Journal Paper
journal: 
Proteins 2014, doi: 10.1002/prot.24714
Url: 
http://onlinelibrary.wiley.com/doi/10.1002/prot.24714/abstract
Date of acceptance: 
2014-11-18
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