Repurposing and repositioning drugs has become a frequently pursued and successful strategy in the current era, as new chemical entities are increasingly difficult to find and get approved. Herein we report an integrated BioGPS/FLAPdock pipeline for rapid and effective off-target identification and drug repurposing. Our method is based on the structural and chemical properties of protein binding sites, that is, the ligand image, encoded in the GRID molecular interaction fields (MIFs). Protein similarity is disclosed through the BioGPS algorithm by measuring the pockets' overlap according to which pockets are clustered. Co-crystallized and known ligands can be cross-docked among similar targets, selected for subsequent in vitro binding experiments, and possibly improved for inhibitory potency. We used human thymidylate synthase (TS) as a test case and searched the entire RCSB Protein Data Bank (PDB) for similar target pockets. We chose casein kinase IIα as a control and tested a series of its inhibitors against the TS template. Ellagic acid and apigenin were identified as TS inhibitors, and various flavonoids were selected and synthesized in a second-round selection. The compounds were demonstrated to be active in the low-micromolar range.
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http://dx.doi.org/10.1002/cmdc.201600121 | DOI Listing |
Int J Biol Macromol
December 2024
Bioinformatics Centre, Savitribai Phule Pune University, Pune 411007, MS (Maharashtra), India. Electronic address:
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a significant global health challenge due to the emergence of drug-resistant strains. This study targets Flavin-dependent thymidylate synthase (ThyX), an essential enzyme in the thymidylate biosynthesis pathway crucial for bacterial DNA replication. We utilized advanced computational techniques, including molecular dynamics (MD) simulations and interaction energy analysis, to examine the binding interactions and stability of various thiazole-thiadiazole compounds with Mtb ThyX.
View Article and Find Full Text PDFJ Fluoresc
December 2024
Department of Studies in Physics, Karnatak University, Dharwad, 580003, Karnataka, India.
In the present work, we report the synthesis of TiO nanoparticles by hydrothermal method using titanium isopropoxide. The synthesized TiO nanoparticles were investigated by Powder X-ray diffraction, FE-SEM with EDX, Photoluminescence, UV-Visible absorption and Fluorescence emission spectroscopy. Fluorescence intensity and absorption values of 4-[5-(2,5-Dimethyl-pyrrol-1-yl)-[1,3,4]thiadiazol-2-ylsulfanylmethyl]-6-methoxy-chromen-2-one (DTYMC) molecule decreases with adding the concentration of TiO nanoparticles.
View Article and Find Full Text PDFFront Pharmacol
November 2024
Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
BJC Rep
November 2024
Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers (Amsterdam UMC), Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
ACS Med Chem Lett
November 2024
School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu 212100, China.
Three 1-deoxynojirimycin (DNJ) derivatives (named -) including DNJ and tegafur (TGF) were designed and synthesized, and their antiproliferative effects were investigated. -, especially , exerted good lipophilicity, α-glucosidase inhibitory activity, and antitumor effects. Mechanism studies indicated that significantly induced cell apoptosis and S-phase block and inhibited migration of HCT-116 cells.
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