On the Paradigm Shift Towards Multitarget Selective Drug Design

Dessalew, Nigus; Mikre, Workalemahu

doi:10.2174/157340908784533229

Cited by 12 publications

(6 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another drawback using drug combinations is that the target space of the current pharmacopeia is limited to approximately 1,200 FDAapproved drugs. The third strategy is to design a single compound acting on multiple targets (74,75). Dosing with a single compound may have advantages over a drug combination in terms of equitable pharmacokinetics and biodistribution.…”

Section: Multi-target Drugsmentioning

confidence: 99%

Systems Biology Approaches and Tools for Analysis of Interactomes and Multi-target Drugs

Schrattenholz

Groebe²,

Šoškić³

2010

Methods in Molecular Biology

View full text Add to dashboard Cite

Systems biology is essentially a proteomic and epigenetic exercise because the relatively condensed information of genomes unfolds on the level of proteins. The flexibility of cellular architectures is not only mediated by a dazzling number of proteinaceous species but moreover by the kinetics of their molecular changes: The time scales of posttranslational modifications range from milliseconds to years. The genetic framework of an organism only provides the blue print of protein embodiments which are constantly shaped by external input. Indeed, posttranslational modifications of proteins represent the scope and velocity of these inputs and fulfil the requirements of integration of external spatiotemporal signal transduction inside an organism. The optimization of biochemical networks for this type of information processing and storage results in chemically extremely fine tuned molecular entities. The huge dynamic range of concentrations, the chemical diversity and the necessity of synchronisation of complex protein expression patterns pose the major challenge of systemic analysis of biological models. One further message is that many of the key reactions in living systems are essentially based on interactions of moderate affinities and moderate selectivities. This principle is responsible for the enormous flexibility and redundancy of cellular circuitries. In complex disorders such as cancer or neurodegenerative diseases, which initially appear to be rooted in relatively subtle dysfunctions of multimodal physiologic pathways, drug discovery programs based on the concept of high affinity/high specificity compounds ("one-target, one-disease"), which has been dominating the pharmaceutical industry for a long time, increasingly turn out to be unsuccessful. Despite improvements in rational drug design and high throughput screening methods, the number of novel, single-target drugs fell much behind expectations during the past decade, and the treatment of "complex diseases" remains a most pressing medical need. Currently, a change of paradigm can be observed with regard to a new interest in agents that modulate multiple targets simultaneously, essentially "dirty drugs." Targeting cellular function as a system rather than on the level of the single target, significantly increases the size of the drugable proteome and is expected to introduce novel classes of multi-target drugs with fewer adverse effects and toxicity. Multiple target approaches have recently been used to design medications against atherosclerosis, cancer, depression, psychosis and neurodegenerative diseases. A focussed approach towards "systemic" drugs will certainly require the development of novel computational and mathematical concepts for appropriate modelling of complex data. But the key is the extraction of relevant molecular information from biological systems by implementing rigid statistical procedures to differential proteomic analytics.

show abstract

Section: Multi-target Drugsmentioning

confidence: 99%

Systems Biology Approaches and Tools for Analysis of Interactomes and Multi-target Drugs

Schrattenholz

Groebe²,

Šoškić³

2010

Methods in Molecular Biology

View full text Add to dashboard Cite

show abstract

“…These stability investigations are complemented by ones that probe whether water molecules can penetrate their β-strand–turn−β-strand motif pore, that is, whether Aβ–amylin assemblies can lead to water leakage through cell membranes, the commonly accepted mechanism of toxicity. While the purpose of this article is to add to a better understanding of the physical mechanism of cross-seeding between amylin and Aβ and of the mechanism for the cell toxicity of the resulting oligomers, it also points to the β 1 and β 2 regions as potential targets for the design of aggregation inhibitors. , …”

mentioning

confidence: 99%

“…While the purpose of this article is to add to a better understanding of the physical mechanism of cross-seeding between amylin and Aβ and of the mechanism for the cell toxicity of the resulting oligomers, it also points to the β 1 and β 2 regions as potential targets for the design of aggregation inhibitors. 31,32 ■ RESULTS AND DISCUSSIONS Structural Stability of Self-and Cross-Seeded Oligomers. An overall picture of the conformational changes over the course of the simulation can be gained by comparing the average structures with the initial one.…”

mentioning

confidence: 99%

In Silico Cross Seeding of Aβ and Amylin Fibril-like Oligomers

Berhanu

Yaşar

Hansmann

2013

ACS Chem. Neurosci.

View full text Add to dashboard Cite

Recent epidemiological data have shown that patients suffering from Type 2 Diabetes Mellitus have an increased risk to develop Alzheimer's disease and vice versa. A possible explanation is the cross-sequence interaction between Aβ and amylin. Because the resulting amyloid oligomers are difficult to probe in experiments, we investigate stability and conformational changes of Aβ−amylin heteroassemblies through molecular dynamics simulations. We find that Aβ is a good template for the growth of amylin and vice versa. We see water molecules permeate the β-strand−turn−β-strand motif pore of the oligomers, supporting a commonly accepted mechanism for toxicity of β-rich amyloid oligomers. Aiming for a better understanding of the physical mechanisms of cross-seeding and cell toxicity of amylin and Aβ aggregates, our simulations also allow us to identify targets for the rational design of inhibitors against toxic fibril-like oligomers of Aβ and amylin oligomers.

show abstract

“…These results suggest that future work on the development of inhibitors should focus not only on the toxic oligomers but also on preventing fibril formation, as fibrils can catalyze the aggregation of the toxic oligomers. Developing such inhibitors that both suppress oligomer toxicity and prevent fibril growth is likely necessary for developing effective therapies against amyloid diseases (Dessalew & Mikre, 2008). A promising start point is cyclic peptides.…”

Section: Discussionmentioning

confidence: 99%