Drug Repurposing and Multi-Target Therapies

Published date : 26 May 2018

Since biological systems are often complex and comprising networks of multiple, interacting genes and their products, polypharmacology-based drug repurposing has gained wider acceptance in recent years. We discuss the benefits and drawbacks of drug repurposing. We list the available computational resources, including databases and algorithms (particularly CLICK), for drug repurposing. We also detail virtual screenings, particularly genomic screenings and high-throughput screenings. Finally, we present the challenges associated with drug repurposing and our proposed solutions.

type
Book/Book Chapter
journal
Reference Module in Life Sciences, 26 May 2018, doi: 10.1016/B978-0-12-809633-8.20160-X,

Stapled peptides as a new technology to investigate protein-protein interactions in human platelets

Published date : 25 May 2018

Platelets are blood cells with numerous crucial pathophysiological roles in hemostasis, cardiovascular thrombotic events and cancer metastasis. Platelet activation requires the engagement of intracellular signalling pathways that involve protein–protein interactions (PPIs). A better understanding of these pathways is therefore crucial for the development of selective anti-platelet drugs. New strategies for studying PPIs in human platelets are required to overcome limitations associated with conventional platelet research methods.

type
Journal Paper
journal
Chemical Science 2018, 9, Pg 4638-4643, doi: 10.1039/c8sc00284c

Impact Factor
8.668

Partial Intrinsic Disorder Governs the Dengue Capsid Protein Conformational Ensemble

Published date : 24 May 2018

The 11 kDa, positively charged dengue capsid protein (C protein) exists stably as a homodimer and co-localizes with the viral genome within mature viral particles. Its core is composed of four alpha helices encompassing a small hydrophobic patch that may interact with lipids, but approximately 20% of the protein at the N-terminus is intrinsically disordered, making it challenging to elucidate its conformational landscape.

type
Journal Paper
journal
ACS Chemical Biology 2018 Jun 15;13(6):1621-1630. doi: 10.1021/acschembio.8b00231
Impact Factor
4.592

Isolation and Identification of an Anthracimycin Analogue from Nocardiopsis kunsanensis, a Halophile from a Saltern, by Genomic Mining Strategy

Published date : 21 May 2018

Modern medicine is unthinkable without antibiotics; yet, growing issues with microbial drug resistance require intensified search for new active compounds. Natural products generated by Actinobacteria have been a rich source of candidate antibiotics, for example anthracimycin that, so far, is only known to be produced by Streptomyces species. Based on sequence similarity with the respective biosynthetic cluster, we sifted through available microbial genome data with the goal to find alternative anthracimycin-producing organisms.

type
Journal Paper
journal
Journal of Genomics, Vol. 6, 2018, Pg 63-73, doi:10.7150/jgen.24368
Impact Factor
2.402

Gene expression profile analysis of aortic vascular smooth muscle cells reveals upregulation of cadherin genes in myocardial infarction patients

Published date : 18 May 2018

Myocardial infarction (MI) induced by acute coronary arterial occlusion is usually secondary to atherosclerotic plaque rupture. Dysregulated response of vascular smooth muscle cells (VSMCs) in atherosclerotic plaques may promote plaque rupture. Cadherins (CDHs) form adherens junctions and are known stabilizers of atherosclerotic plaques. To date, the expression patterns of cadherin have not been well investigated in MI aortic VSMCs. We aimed to investigate the expression of cadherin genes in the aortic wall of patients with and without MI.

type
Journal Paper
journal
Physiological Genomics, 18 May 2018, doi: 10.1152/physiolgenomics.00042.2017
Impact Factor
2.782

Antimicrobial activity profiles of Amphiphilic Xanthone derivatives are a function of their molecular Oligomerization

Published date : 18 May 2018

Currently, membrane-targeting small antimicrobial peptidomimetics (SAP) are important in antibiotic development because bacteria appear to develop resistance to these surface-active compounds less readily. However, the molecular membrane-targeting action of SAPs has received little attention. In this study, we investigated the effect of oligomerization of amphiphilic xanthone, a model SAP, on its antimicrobial properties against both Gram-positive and Gram-negative bacteria.

type
Journal Paper
journal
Biochimica et Biophysica Acta (BBA) - Biomembranes, 2018, doi: 10.1016/j.bbamem.2018.05.006
Impact Factor
3.498

A Thermodynamic Funnel Drives Bacterial Lipopolysaccharide Transfer in the TLR4 Pathway

Published date : 17 May 2018

The Gram-negative bacterial outer membrane contains lipopolysaccharide, which potently stimulates the mammalian innate immune response. This involves a relay of specialized complexes culminating in transfer of lipopolysaccharide from CD14 to Toll-like receptor 4 (TLR4) and its co-receptor MD-2 on the cell surface, leading to activation of downstream inflammatory responses. In this study we develop computational models to trace the TLR4 cascade in near-atomic detail.

type
Journal Paper
journal
Structure, 26, Pg 1-11, July 3, 2018, doi: 10.1016/j.str.2018.04.007
Impact Factor
4.907

Conformational landscape of the epidermal growth factor receptor kinase reveals a mutant specific allosteric pocket

Published date : 16 May 2018

Activating mutations within the epidermal growth factor receptor (EGFR) kinase domain give rise to several cancers including Non-Small Cell Lung Cancer (NSCLC). Small molecule inhibitors targeted at these mutants have proven to be clinically successful drugs. These molecules are ATP competitive and rapidly result in the emergence of resistance. Recently Jia et al.

type
Journal Paper
journal
Chemical Science, 2018, doi: 10.1039/C8SC01262H
Impact Factor
8.668

Function of a membrane-embedded domain evolutionarily multiplied in the GPI lipid anchor pathway proteins PIG-B, PIG-M, PIG-U, PIG-W, PIG-V, and PIG-Z

Published date : 15 May 2018

Distant homology relationships among proteins with many transmembrane regions (TMs) are difficult to detect as they are clouded by the TMs’ hydrophobic compositional bias and mutational divergence in connecting loops. In the case of several GPI lipid anchor biosynthesis pathway components, the hidden evolutionary signal can be revealed with dissectHMMER, a sequence similarity search tool focusing on fold-critical, high complexity sequence segments.

type
Journal Paper
journal
Cell Cycle, Vol 17, 2018, Issue 7, doi: 10.1080/15384101.2018.1456294
Impact Factor
3.304

Function of a membrane-embedded domain evolutionarily multiplied in the GPI lipid anchor pathway proteins PIG-B, PIG-M, PIG-U, PIG-W, PIG-V, and PIG-Z

Published date : 15 May 2018

Distant homology relationships among proteins with many transmembrane regions (TMs) are difficult to detect as they are clouded by the TMs’ hydrophobic compositional bias and mutational divergence in connecting loops. In the case of several GPI lipid anchor biosynthesis pathway components, the hidden evolutionary signal can be revealed with dissectHMMER, a sequence similarity search tool focusing on fold-critical, high complexity sequence segments.

type
Journal Paper
journal
Cell Cycle, Vol 17, 2018, Issue 7, doi: 10.1080/15384101.2018.1456294
Impact Factor
3.304