Synthesis of SARS-CoV-2 M^pro inhibitors bearing a cinnamic ester warhead with in vitro activity against human coronaviruses

Organic & Biomolecular Chemistry, Journal Year: 2023, Volume and Issue: 21(18), P. 3811 - 3824

Published: Jan. 1, 2023

A panel of novel cinnamic ester derivatives showed a potent inhibitory effect against SARS-CoV-2 M pro and efficiently impaired the in vitro replication two human coronaviruses low micromolar range.

Language: Английский

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Targeted Screening of Curcumin Derivatives as Pancreatic Lipase Inhibitors Using Computer-Aided Drug Design

ACS Omega, Journal Year: 2024, Volume and Issue: 9(25), P. 27669 - 27679

Published: June 13, 2024

Curcumin has demonstrated promising preclinical antiobesity effects, but its low bioavailability makes it difficult to exert full effect at a suitable dose. The objective of this study was screen curcumin derivatives with enhanced and lipid-lowering activity under the guidance computer-aided drug design (CADD). CAAD used perform virtual assays on assess their pharmacokinetic properties effects pancreatic lipase activity. Subsequently, 19 containing 5 skeletons were synthesized confirm above assay. in vitro inhibition assay employed determine half-maximal inhibitory concentration (IC50) these derivatives. Based CADD analysis inhibition, 2 outperformed both aspects. Microscale thermophoresis (MST) experiments binding equilibrium constants (Kd) aforementioned derivatives, curcumin, positive control lipase. Through screening utilizing chemoinformatics database molecular docking, 6 superior solubility, absorption, compared curcumin. IC50 value for 1,7-bis(4-hydroxyphenyl)heptane-3,5-dione (C4), which displayed most effective effect, 42.83 μM, while 1,7-bis(4-hydroxy-3-methoxyphenyl)heptane-3,5-dione (C6) 98.62 μM. On other hand, 142.24 MST experiment results indicated that Kd values C4, C6, 2.91, 18.20, 23.53 respectively. exhibited relatively high degree concordance outcomes yielded by screening. Under CADD, targeted excellent high-efficiency low-cost benefits.

Language: Английский

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Computational Design of Novel Cyclic Peptides Endowed with Autophagy-Inhibiting Activity on Cancer Cell Lines

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(9), P. 4622 - 4622

Published: April 24, 2024

(1) Autophagy plays a significant role in development and cell proliferation. This process is mainly accomplished by the LC3 protein, which, after maturation, builds nascent autophagosomes. The inhibition of maturation results interference autophagy activation. (2) In this study, starting from structure known LC3B binder (LIR2-RavZ peptide), we identified new ligands applying an silico drug design strategy. most promising peptides were synthesized, biophysically assayed, biologically evaluated to ascertain their potential antiproliferative activity on five humans lines. (3) A cyclic peptide (named Pep6), endowed with high conformational stability (due presence disulfide bridge), displayed Kd value nanomolar range. Assays PC3, MCF-7, A549 cancer lines proved that Pep6 exhibited cytotoxic effects comparable those LIR2-RavZ, reference ligand. Furthermore, it was ineffective both normal prostatic epithelium PNT2 autophagy-defective prostate DU145 cells. (4) can be considered inhibitor employed as pharmacological tool or even template for rational small molecules inhibitory activity.

Language: Английский

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Synthesis of α-fluorocinnamate derivatives as novel cathepsin S inhibitors with in vitro antiproliferative activity against pancreatic cancer cells

Bioorganic & Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 115, P. 117987 - 117987

Published: Nov. 5, 2024

Language: Английский

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Development of AMBER Parameters for Molecular Simulations of Selected Boron-Based Covalent Ligands

Molecules, Journal Year: 2023, Volume and Issue: 28(6), P. 2866 - 2866

Published: March 22, 2023

Boron containing compounds (BCCs) aroused increasing interest in the scientific community due to their wide application as drugs various fields. In order design new hopefully endowed with pharmacological activity and also investigate conformational behavior, support of computational studies is crucial. Nevertheless, suitable molecular mechanics parameterization force fields needed perform these simulations are not completely available for this class molecules. paper, Amber field parameters phenyl-, benzyl-, benzylamino-, methylamino-boronates, a group boron-containing involved different branches medicinal chemistry, were created. The robustness obtained data was confirmed through dynamics on ligand/β-lactamases covalent complexes. ligand torsional angles, populated over trajectory frames, by values found geometries, located optimizations at DFT/B3LYP/6-31g(d) level, using water solvent. summary, study successfully provided library parameters, opening possibility compounds.

Language: Английский

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Engineered Therapeutic Antibody Against SARS-CoV-2

Current Clinical Microbiology Reports, Journal Year: 2023, Volume and Issue: 10(4), P. 222 - 235

Published: Nov. 14, 2023

Language: Английский

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