International Journal of Molecular Sciences

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Dear Colleagues,

Developing a new drug from an original hit to the launch of an approved product is a complex process which can take 12–15 years and cost in excess of USD 1–2 billion. The idea for a novel target can come from a variety of sources, including clinical research, phenotypic studies, structural biology, and from the application of in silico methods. It may take many years to sufficiently validate a target to start a costly drug discovery programme. Once a target has been validated, numerous processes have to be carried out to identify molecules which possess suitable characteristics to make acceptable drug candidates for clinical studies. The application of in silico methods, including structure-based design, molecular dynamics simulations, artificial intelligence and machine learning, has become an essential part of the early drug-discovery process. A breakthrough in structure-based design is certainly a recent development of the deep-learning approach AlphaFold for the 3D structure prediction of new proteins. However, the development of numerous biophysical and functional assay methods could also help to drive the selection of suitable targets and lead compounds.

Targeted protein degradation in cells via novel chemical compounds such as proteolysis-targeting chimeras (PROTACs) is considered one of the promising techniques in medicinal chemistry and early drug discovery. PROTACs are designed to degrade target proteins by harnessing the ubiquitin-proteasome system, and may thus offer new ways to circumvent some of the limitations associated with traditional small-molecule therapeutics.

Recent examples of medicinal chemistry and early drug discovery include novel targets from cancer epigenetics, tumor microenvironment, cancer immunology, as well as transcription factors, previously underexplored kinases, and RNA. Even proteins previously considered undruggable, such as c-Myc, transcription factors, and RNA/DNA-binding proteins, are now being targeted with novel approaches such as covalent chemical probes and PROTACs. The purpose of this Special Issue is to present current efforts in medicinal chemistry and early drug discovery. Original research articles, review articles, and short communications within (but not limited to) the research areas described are welcome.

Dr. Wolfgang Sippl
Guest Editor

Manuscript Submission Information

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Keywords

medicinal chemistry
drug discovery
computer-assisted drug design
drug targets
machine learning
epigenetic targets
in vitro assays
biophysical methods
target engagement studies
multi-targeting compounds
PROTAC

Published Papers (2 papers)

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Research

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16 pages, 2541 KiB

Open AccessArticle

Turning a Tumor Microenvironment Pitfall into Opportunity: Discovery of Benzamidoxime as PD-L1 Ligand with pH-Dependent Potency

by Elisa Bianconi, Alessandra Riccio, Luana Ruta, Carlo Bigiotti, Andrea Carotti, Sonia Moretti, Bruno Cerra, Antimo Gioiello, Simone Ferlin, Efisio Puxeddu and Antonio Macchiarulo

Int. J. Mol. Sci. 2023, 24(6), 5535; https://doi.org/10.3390/ijms24065535 - 14 Mar 2023

Cited by 3 | Viewed by 1400

Abstract

PD-1/PD-L1 protein complex is attracting a great deal of interest as a drug target for the design of immune therapies able to block its assembly. Although some biologic drugs have entered clinical use, their poor response rate in patients are demanding further efforts to design small molecule inhibitors of PD-1/PD-L1 complex with higher efficacy and optimal physicochemical properties. Dysregulation of pH in the tumor microenvironment is indeed one of the key mechanisms promoting drug resistance and lack of response in cancer therapy. Integrating computational and biophysical approaches, herein we report a screening campaign that has led to identifying VIS310 as a novel ligand of PD-L1, with physicochemical properties enabling a pH-dependent binding potency. Additional optimization efforts by analogue-based screening have been instrumental to disclosing VIS1201, which exhibits improved binding potency against PD-L1 and is able to inhibit PD-1/PD-L1 complex formation in a ligand binding displacement assay. While providing preliminary structure–activity relationships (SARs) of a novel class of PD-L1 ligands, our results lay the foundation for the discovery of immunoregulatory small molecules resilient to tumor microenvironmental conditions for escaping drug-resistance mechanisms. Full article

(This article belongs to the Special Issue Early-Stage Drug Discovery: Advances and Challenges 2.0)

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Review

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20 pages, 2681 KiB

Open AccessReview

GSK-3β Allosteric Inhibition: A Dead End or a New Pharmacological Frontier?

by Beatrice Balboni, Mirco Masi, Walter Rocchia, Stefania Girotto and Andrea Cavalli

Int. J. Mol. Sci. 2023, 24(8), 7541; https://doi.org/10.3390/ijms24087541 - 19 Apr 2023

Cited by 5 | Viewed by 1957

Abstract

Most kinase inhibitors are designed to bind to highly homologous ATP-binding sites, which leads to promiscuity and possible off-target effects. Allostery is an alternative approach to pursuing selectivity. However, allostery is difficult to exploit due to the wide variety of underlying mechanisms and the potential involvement of long-range conformational effects that are difficult to pinpoint. GSK-3β is involved in several pathologies. This critical target has an ATP-binding site that is highly homologous with the orthosteric sites of other kinases. Unsurprisingly, there is also great similarity between the ATP-binding sites of GSK-3β and its isomer, which is not redundant and thus would benefit from selective inhibition. Allostery would also allow for a moderate and tunable inhibition, which is ideal for GSK-3β, because this target is involved in multiple pathways, some of which must be preserved. However, despite considerable research efforts, only one allosteric GSK-3β inhibitor has reached the clinic. Moreover, unlike other kinases, there are no X-ray structures of GSK-3β in complex with allosteric inhibitors in the PDB data bank. This review aims to summarize the state of the art in allosteric GSK-3β inhibitor investigations, highlighting the aspects that make this target challenging for an allosteric approach. Full article

(This article belongs to the Special Issue Early-Stage Drug Discovery: Advances and Challenges 2.0)

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