After a decade of approval of the drug vemurafenib in 2011, the hopeless scenario imposed by some severe cancer types has been mitigated by the magic bullets developed through fragment-based drug discovery. Moreover, this recent approach to medicinal chemistry has been successfully practiced by academic laboratories and pharmaceutical industry workflows focused on drug design with an enhanced profile for chemotherapy of aggressive tumors. This mini-review highlights the successes achieved by these research campaigns in the fruitful field of the molecular fragment paradigm that resulted in the approval of six new anticancer drugs in the last decade (2011-2021), as well as several promising clinical candidates. It is a particularly encouraging opportunity for other researchers who want to become aware of the applicability and potency of this new paradigm applied to the design and development of powerful molecular weapons in the constant war against these merciless scourges of humanity.
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http://dx.doi.org/10.2174/1871520623666230714163823 | DOI Listing |
Angew Chem Int Ed Engl
December 2024
Goethe-Universitat Frankfurt am Main Fachbereich 14 Biochemie Chemie und Pharmazie, Institute for Pharmaceutical Chemistry, GERMANY.
Protein kinases are important drug targets, yet specific inhibitors have been developed for only a fraction of the more than 500 human kinases. A major challenge in designing inhibitors for highly related kinases is selectivity. Unlike their non-covalent counterparts, covalent inhibitors offer the advantage of selectively targeting structurally similar kinases by modifying specific protein side chains, particularly non-conserved cysteines.
View Article and Find Full Text PDFJ Biomol Struct Dyn
December 2024
Amity Institute of Biotechnology, Amity University, Kolkata, India.
The first FDA approved, MDR-TB inhibitory drug bedaquiline (BDQ), entraps the c-ring of the proton-translocating F region of enzyme ATP synthase of , thus obstructing successive ATP production. Present-day BDQ-resistance has been associated with cardiotoxicity and mutation(s) in the atpE gene encoding the c subunit of ATP synthase (ATPc) generating five distinct ATPc mutants: Ala63→Pro, Ile66→Met, Asp28→Gly, Asp28→Val and Glu61→Asp. We created three discrete libraries, first by repurposing bedaquiline via scaffold hopping approach, second one having natural plant compounds and the third being experimentally derived analogues of BDQ to identify one drug candidate that can inhibit ATPc activity more efficiently with less toxic properties.
View Article and Find Full Text PDFMolecules
December 2024
Experimental Drug Development Centre (EDDC), Agency for Science, Technology and Research (A*STAR), 10 Biopolis Road, #05-01, Singapore 138670, Singapore.
Fragment-based drug discovery is a powerful approach in drug discovery, applicable to a wide range of targets. This method enables the discovery of potent compounds that can modulate target functions, starting from fragment compounds that bind weakly to the targets. While biochemical, biophysical, and cell-based assays are commonly used to identify fragments, F-NMR spectroscopy has emerged as a powerful tool for exploring interactions between biomolecules and ligands.
View Article and Find Full Text PDFAngew Chem Int Ed Engl
December 2024
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Drug Design and Optimization, Campus E8.1, 66123, Saarbrücken, GERMANY.
With antimicrobial resistance (AMR) reaching alarming levels, new anti-infectives with unpreceded mechanisms of action are urgently needed. The 2-C-methylerythritol-D-erythritol-4-phosphate (MEP) pathway represents an attractive source of drug targets due to its essential role in numerous pathogenic Gram-negative bacteria and Mycobacterium tuberculosis (Mt), whilst being absent in human cells. Here, we solved the first crystal structure of Pseudomonas aeruginosa (Pa) IspD, the third enzyme in the MEP pathway and present the discovery of a fragment-based compound class identified through crystallographic screening of PaIspD.
View Article and Find Full Text PDFJ Sep Sci
December 2024
Department of Laboratory Medicine, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao, P. R. China.
Sweroside, a natural secoiridoid glycoside derived from various medicinal plants, is known for its anti-tumor, anti-inflammatory, and hepatoprotective properties. However, its pharmacological significance is not fully supported by its low systemic exposure. In this study, a de novo strategy was proposed to investigate the metabolism of sweroside in rats, including drug administration, sample pretreatment, ultra-high-performance liquid chromatography/Quadrupole-Exactive mass spectrometry data acquisition, data processing, and semi-quantitative analysis.
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