| 1. |
- Thanh Le, Thanh, et al.
(author)
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Diarylether-Amino Acid Conjugates as New Class of Anticancer Agents
- 2023
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In: CHEMISTRYSELECT. - : Wiley. - 2365-6549. ; 8:28
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Journal article (peer-reviewed)abstract
- Diarylether (DE) is a privileged structure found in both natural products and synthetic compounds including small molecule drugs. We present the synthesis of a series of 13 new DE-amino acid conjugates which were screened for cancer cells antiproliferation activity. Structure-activity relationship suggests ester and phenyl groups in DE-Phe-OEt 4 c are important for the activity. Compound 4 c inhibited strongly MCF-7 3D tumor sphere formation and have favourable calculated physical chemical properties according to Lipinski's rule of 5. Docking study suggests estrogen receptor and/ or 3a-HSD type 3 protein could be the target(s) for anticancer activity of this class of compounds.
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| 2. |
- Pham, Em Canh, et al.
(author)
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N,2,6-Trisubstituted 1H-benzimidazole derivatives as a new scaffold of antimicrobial and anticancer agents : design, synthesis, in vitro evaluation, and in silico studies
- 2023
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In: RSC Advances. - : Royal Society of Chemistry. - 2046-2069. ; 13:1, s. 399-420
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Journal article (peer-reviewed)abstract
- Compounds containing benzimidazole moiety occupy privileged chemical space for discovering new bioactive substances. In continuation of our recent work, 69 benzimidazole derivatives were designed and synthesized with good to excellent yields of 46-99% using efficient synthesis protocol i.e. sodium metabisulfite catalyzed condensation of aromatic aldehydes with o-phenylenediamines to form 2-arylbenzimidazole derivatives followed by N-alkylation by conventional heating or microwave irradiation for diversification. Potent antibacterial compounds against MSSA and MRSA were discovered such as benzimidazole compounds 3k (2-(4-nitrophenyl), N-benzyl), 3l (2-(4-chlorophenyl), N-(4-chlorobenzyl)), 4c (2-(4-chlorophenyl), 6-methyl, N-benzyl), 4g (2-(4-nitrophenyl), 6-methyl, N-benzyl), and 4j (2-(4-nitrophenyl), 6-methyl, N-(4-chlorobenzyl)) with MIC of 4-16 mu g mL(-1). In addition, compound 4c showed good antimicrobial activities (MIC = 16 mu g mL(-1)) against the bacteria strains Escherichia coli and Streptococcus faecalis. Moreover, compounds 3k, 3l, 4c, 4g, and 4j have been found to kill HepG2, MDA-MB-231, MCF7, RMS, and C26 cancer cells with low mu M IC50 (2.39-10.95). These compounds showed comparable drug-like properties as ciprofloxacin, fluconazole, and paclitaxel in computational ADMET profiling. Finally, docking studies were used to assess potential protein targets responsible for their biological activities. Especially, we found that DHFR is a promising target both in silico and in vitro with compound 4c having IC50 of 2.35 mu M.
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| 3. |
- Matricon, Pierre, et al.
(author)
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Structure-based virtual screening discovers potent and selective adenosine A1 receptor antagonists
- 2023
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In: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 257
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Journal article (peer-reviewed)abstract
- Development of subtype-selective leads is essential in drug discovery campaigns targeting G protein-coupled receptors (GPCRs). Herein, a structure-based virtual screening approach to rationally design subtype-selective ligands was applied to the A1 and A2A adenosine receptors (A1R and A2AR). Crystal structures of these closely related subtypes revealed a non-conserved subpocket in the binding sites that could be exploited to identify A1R selective ligands. A library of 4.6 million compounds was screened computationally against both receptors using molecular docking and 20 A1R selective ligands were predicted. Of these, seven antagonized the A1R with micromolar activities and several compounds displayed slight selectivity for this subtype. Twenty-seven analogs of two discovered scaffolds were designed, resulting in antagonists with nanomolar potency and up to 76-fold A1R-selectivity. Our results show the potential of structure-based virtual screening to guide discovery and optimization of subtype-selective ligands, which could facilitate the development of safer drugs.
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| 4. |
- Panel, Nicolas, et al.
(author)
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Design of Drug Efficacy Guided by Free Energy Simulations of the β2-Adrenoceptor
- 2023
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In: Angewandte Chemie International Edition. - : Wiley. - 1433-7851 .- 1521-3773. ; 62:22
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Journal article (peer-reviewed)abstract
- G-protein-coupled receptors (GPCRs) play important roles in physiological processes and are modulated by drugs that either activate or block signaling. Rational design of the pharmacological efficacy profiles of GPCR ligands could enable the development of more efficient drugs, but is challenging even if high-resolution receptor structures are available. We performed molecular dynamics simulations of the β2 adrenergic receptor in active and inactive conformations to assess if binding free energy calculations can predict differences in ligand efficacy for closely related compounds. Previously identified ligands were successfully classified into groups with comparable efficacy profiles based on the calculated shift in ligand affinity upon activation. A series of ligands were then predicted and synthesized, leading to the discovery of partial agonists with nanomolar potencies and novel scaffolds. Our results demonstrate that free energy simulations enable design of ligand efficacy and the same approach can be applied to other GPCR drug targets.
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| 5. |
- Sethio, Daniel, et al.
(author)
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Simulation Reveals the Chameleonic Behavior of Macrocycles
- 2023
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In: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 63:1, s. 138-146
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Journal article (peer-reviewed)abstract
- Conformational analysis is central to the design of bioactive molecules. It is particularly challenging for macrocycles due to noncovalent transannular interactions, steric interactions, and ring strain that are often coupled. Herein, we simulated the conformations of five macrocycles designed to express a progression of increasing complexity in environment-dependent intramolecular interactions and verified the results against NMR measurements in chloroform and dimethyl sulfoxide. Molecular dynamics using an explicit solvent model, but not the Monte Carlo method with implicit solvation, handled both solvents correctly. Refinement of conformations at the ab initio level was fundamental to reproducing the experimental observations-standard state-of-the-art molecular mechanics force fields were insufficient. Our simulations correctly predicted the intramolecular interactions between side chains and the macrocycle and revealed an unprecedented solvent-induced conformational switch of the macrocyclic ring. Our results provide a platform for the rational, prospective design of molecular chameleons that adapt to the properties of the environment.
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