Atomistic Simulations and Design in Biology

Preclinical Characteristics of the Irreversible Pan-HER Kinase Inhibitor Neratinib Compared with Lapatinib: Implications for the Treatment of HER2-Positive and HER2-Mutated Breast Cancer

Published date : 28 May 2019

An estimated 15–20% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2/ERBB2/neu). Two small-molecule tyrosine kinase inhibitors (TKIs), lapatinib and neratinib, have been approved for the treatment of HER2-positive (HER2+) breast cancer.

type
Journal Paper
journal
Cancers 2019, Vol. 11, Issue 6, 37, doi: 10.3390/cancers11060737
Impact Factor
5.326

Exploring Gatekeeper Mutations in EGFR through Computer Simulations

Published date : 17 May 2019

The emergence of resistance against drugs that inhibit a particular protein is a major problem in targeted therapy. There is a clear need for rigorous methods to predict the likelihood of specific drug-resistance mutations arising in response to the binding of a drug. In this work we attempt to develop a robust computational protocol for predicting drug resistant mutations at the gatekeeper position (T790) in EGFR. We explore how mutations at this site affects interactions with ATP and three drugs that are currently used in clinics. We found, as expected,

type
Journal Paper
journal
Journal of Chemical Information and Modeling, 2019, doi: 10.1021/acs.jcim.9b00361
Impact Factor
3.804

AppA: a web server for analysis, comparison, and visualization of contact residues and interfacial waters of antibody–antigen structures and models

Published date : 09 May 2019

The study of contact residues and interfacial waters of antibody–antigen (Ab-Ag) structures could help in understanding the principles of antibody–antigen interactions as well as provide guidance for designing antibodies with improved affinities. Given the rapid pace with which new antibody–antigen structures are deposited in the protein databank (PDB), it is crucial to have computational tools to analyze contact residues and interfacial waters, and investigate them at different levels.

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Journal Paper
journal
Nuclei Acids Research, 2019, doi: 10.1093/nar/gkz358
Impact Factor
11.561

Efficient development of stable and highly functionalised peptides targeting the CK2a/CK2b protein–protein interaction†

Published date : 12 Apr 2019

The discovery of new Protein–Protein Interaction (PPI) modulators is currently limited by the difficulties associated with the design and synthesis of selective small molecule inhibitors. Peptides are a potential solution for disrupting PPIs; however, they typically suffer from poor stability in vivo and limited tissue penetration hampering their wide spread use as new chemical biology tools and potential therapeutics.

type
Journal Paper
journal
Chemical Science, 2019, 10, 5056-5063, doi: 10.1039/c9sc00798a
Impact Factor
9.063

Inhibition of the NLRP3 inflammasome activation by cell-permeable stapled peptides

Published date : 20 Mar 2019

Interleukin-1β (IL-1β) is a major cytokine that initiates and enhances inflammatory responses. Excessive IL-1β production is a characteristic of most chronic inflammatory diseases, including atherosclerosis, type 2 diabetes, and obesity, which affect a large proportion of the global population. The production of bioactive IL-1β is mediated by a caspase-1-activating complex known as an ‘inflammasome’. The NLRP3 inflammasome has been associated with several human inflammatory and autoimmune diseases and represents a potential therapeutic target for disrupting IL-1β production.

type
Journal Paper
journal
Scientific Reports 9, Article no. 4913 (2019), doi: 10.1038/s41598-019-41211-3
Impact Factor
4.122

"Inhibiting S100B(ββ) for Activating Wild-Type p53: Design of Stapled Peptides"

Published date : 14 Mar 2019

S100B(ββ) is a member of the S100B protein family and is distributed in a cell-specific manner. Its levels are elevated in several cancers such as malignant melanoma and correlate directly with poor prognosis in patients. S100B(ββ) directly interacts with the tumor suppressor p53, inhibiting tetramerization and protein kinase C-dependent phosphorylation, consequently decreasing p53 DNA binding and transcriptional activity, and preventing apoptosis. Thus, S100B(ββ) is being pursued as a target for therapeutic inhibition.

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Journal Paper
journal
ACS Omega 2019, 5, Pg 5335-5344, doi: 10.1021/acsomega.9b00097

An inter-subunit protein-peptide interface that stabilizes the specific activity and oligomerization of the AAA+ chaperone Reptin

Published date : 09 Mar 2019

Reptin is a member of the AAA+ superfamily whose members can exist in equilibrium between monomeric apo forms and ligand bound hexamers. Inter-subunit protein-protein interfaces that stabilize Reptin in its oligomeric state are not well-defined. A self-peptide binding assay identified a protein-peptide interface mapping to an inter-subunit “rim” of the hexamer bridged by Tyrosine-340. A Y340A mutation reduced ADP-dependent oligomer formation using a gel filtration assay, suggesting that Y340 forms a dominant oligomer stabilizing side chain.

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Journal Paper
journal
Journal of Proteomics, Vol. 199, 2019, Pg 89-101 doi:10.1016/j.jprot.2019.02.012
Impact Factor
3.722

Discovering Putative Protein Targets of Small Molecules: A Study of the p53 Activator Nutlin

Published date : 22 Feb 2019

Small molecule drugs bind to a pocket in disease causing target proteins based on complementarity in shape and physicochemical properties. There is a likelihood that other proteins could have binding sites that are structurally similar to the target protein. Binding to these other proteins could alter their activities leading to off target effects of the drug. One such small molecule drug Nutlin binds the protein MDM2, which is upregulated in several types of cancer and is a negative regulator of the tumor suppressor protein p53.

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Journal Paper
journal
Journal of Chemical Information and Modeling, 2019. 59, (4) Pg. 1529-1546, doi: 10.1021/acs.jcim.8b00762
Impact Factor
3.804

Roles of computational modelling in understanding p53 structure, biology, and its therapeutic targeting

Published date : 06 Feb 2019

The multi-faceted role of the transcription factor p53 is key to numerous biological processes, including the suppression of tumours. The availability since the 1990s of a richness of biophysical data aimed at understanding its structure-function relationships has enabled the application of a variety of atomistic computational modelling techniques towards the establishment of mechanistic models. Together they have provided deep insights into the structure, mechanics, energetics, and dynamics of p53.

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Journal Paper
journal
Journal of Molecular Cell Biology, 2019, 11(4), Pg 306-316, doi: 10.1093/jmcb/mjz009
Impact Factor
5.595

Kinetic and thermodynamic effects of phosphorylation on p53 binding to MDM2

Published date : 24 Jan 2019

p53 is frequently mutated in human cancers. Its levels are tightly regulated by the E3 ubiquitin ligase MDM2. The complex between MDM2 and p53 is largely formed by the interaction between the N-terminal domain of MDM2 and the N-terminal transactivation (TA) domain of p53 (residues 15-29). We investigated the kinetic and thermodynamic basis of the MDM2/p53 interaction by using wild-type and mutant variants of the TA domain. We focus on the effects of phosphorylation at positions Thr18 and Ser20 including their substitution with phosphomimetics.

type
Journal Paper
journal
Scientific Reports 9, Article no: 693 (2019). doi: 10.1038/s41598-018-36589-5
Impact Factor
4.122