Special Issue "Hit Generation and Verification for Novel Lead Compounds"
Deadline for manuscript submissions: 30 June 2018
Identifying quality hit compounds in drug discovery projects is a crucial step towards a clinical candidate. Without viable hits against the chosen target, no further progress can be made. A host of approaches have been developed to generate hits, e.g., various screening technologies, as well as traditional bioprospecting. After a hit has been found, a preliminary structure activity relationship (SAR) needs to be established against the target using biochemical and/or biophysical assays. Ligands can either be procured from commercially available compound collections using similarity methods or synthesized. Furthermore, the ligands must lie in a favorable region of chemical space. The SAR results can be checked using molecular modelling against the crystal structure of the target. Finally, cell-based assays are used to test the efficacy of the ligands verifying that their target can be modulated with a small molecule and indeed effects a desirable biological response such as apoptosis for anticancer drug development, i.e., the target is druggable.
A linear process is described here but more often than not it is very convoluted, e.g., the hypothesised target does not respond to the ligands but an excellent efficacy is observed in cell based assays or the activity of the hit is found in a cell based screen and the target needs to be identified. To complicate the process even further, many ligands modulate a host of different targets and finally the nebulous concepts of serendipity needs, somehow, to be considered.
In this Special Issue we wish to focus on the area in drug discovery where hits are identified and verified creating viable leads, laying the foundation for successful development of drug candidates.Dr. Jóhannes Reynisson FRSC
Manuscript Submission Information
Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.
Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access monthly journal published by MDPI.
Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.
- Screening – high throughput; virtual; fragment based
- Similarity searching
- Chemical space
- Structural activity Relationship (SAR)
- Biochemical assays
- Biophysical assays
- Cell based assays
The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.
Title: Development of an in vitro screening platform for the identification of partial PPARγ agonists as a source for antidiabetic lead compounds
Authors: Lars Porskjær Christensen 1,* and Rime Bahji El-Houri 2
Affiliations: 1 Department of Chemistry and Bioscience, Faculty of Engineering and Science, Aalborg University, Fredrik Bajers Vej 7H, 9220 Aalborg Ø, Denmark; firstname.lastname@example.org
2 Department of Chemical Engineering, Biotechnology and Environmental Technology, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark; email@example.com
* Correspondence: firstname.lastname@example.org; Tel.: +45-277-874-94
Abstract: Type 2 diabetes (T2D) is a metabolic disorder where insulin sensitive tissues show reduced sensitivity towards insulin and a decreased glucose uptake (GU), which leads to hyperglycaemia. Peroxisome proliferator-activated receptor (PPAR)γ plays an important role in lipid and glucose homeostasis and is one of the targets in the discovery of drugs against T2D. Activation of PPARγ by agonists leads to a conformational change in the ligand-binding domain altering the transcription of several target genes involved in glucose and lipid metabolism. Depending on the ligands, they can induce different sets of genes that depends of their recruitment of coactivators. The activation of PPAR
Title: A high-content zebrafish chemical screen reveals new enhancers of Fgf/Ras/Mapk signaling as probes for zebrafish heart development.
Author: Michael Wai Kok Tsang; email@example.com
Abstract: Zebrafish is the preferred vertebrate model for high throughput chemical screens to discover modulators of complex biological pathways. We adapted a transgenic zebrafish line, Tg(dusp6:EGFP), which reports on Fibroblast Growth Factor (Fgf)/Ras/Mapk activity, into a quantitative, high-content chemical screen to identify novel Fgf hyperactivators as chemical probes for embryonic development. We screened over 10,000 compounds from the TIMTEC Diversity Set and identified five structurally distinct classes of molecules that enhanced Fgf/Ras/Mapk signaling in the developing larvae. We chose three agents, PT6994, PT20101, and PT11282, for confirmatory and functional studies based on potency, repeatability with authentic material, favorable toxicity profiles, and evidence of structure-activity relationships. All three compounds induced expression of Fgf target genes during zebrafish embryonic development. Moreover, embryos treated with these compounds converted neighboring endothelial progenitors into cardiac progenitors that translated into increased cardiomyocyte numbers. Interestingly, PT6994 hyperactivated Fgf signaling in the absence of Erk phosphorylation, suggesting a molecular mechanism of action downstream of Mapks. We posit that the PT6994 pharmacophore could become a unique chemical probe to uncover novel mechanisms of Fgf/Ras/Mapk signaling during heart development.