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New thymol and carvacrol derivatives with the carbamate moiety were synthesized and their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were evaluated. 5-isopropyl-2-methylphenyl(3-fluorophenyl)carbamate ( 29 ) was found to be the most potent AChE inhibitor with IC 50 values of 2.22 μM, and 5-isopropyl-2-methylphenyl (4-fluorophenyl)carbamate ( 30 ) exhibited the strongest inhibition against BuChE with IC 50 value of 0.02 μM. Additionally, the result of H4IIE hepatoma cell toxicity assay for compounds 18 , 20 , 29 , 30 and 35 showed negligible cell death at 0.07–10 μM. Moreover in order to better understand the inhibitory profiles of these molecules, molecular modeling studies were applied. Binding poses of studied compounds at the binding pockets of AChE and BuChE targets were determined. Predicted binding energies of these compounds as well as structural and dynamical profiles of molecules at the target sites were estimated using induced fit docking (IFD) algorithms and post-processing molecular dynamics (MD) simulations methods (i.e., Molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) approaches). [ABSTRACT FROM AUTHOR]

Novel series of naphthyl bearing 1,2,3-triazoles ( 4a – t ) were synthesized and evaluated for their in vitro antiplasmodial activity against pyrimethamine (Pyr)-sensitive and resistant strains of Plasmodium falciparum. The synthesized compounds were assessed for their cytotoxicity employing human embryonic kidney cell line (HEK-293), and none of them was found to be toxic. Among them 4j , 4k , 4l , 4m , 4n , 4t exhibited significant antiplasmodial activity in both strains, of which compounds 4m , 4n and 4t (∼3.0-fold) displayed superior activity to Pyr against resistant strain. Pyr and selected compounds ( 4n , 4p and 4t ) that repressed parasite development also inhibited PfDHFR activity of the soluble parasite extract, suggesting that anti-parasitic activity of these compounds is a result of inhibition of the parasite DHFR. In silico studies suggest that activity of these compounds might be enhanced due to π-π stacking. [ABSTRACT FROM AUTHOR]

While enzalutamide and abiraterone are approved for treatment of metastatic castration-resistant prostate cancer (mCRPC), approximately 20–40% of patients have no response to these agents. It has been stipulated that the lack of response and the development of secondary resistance to these drugs may be due to the presence of AR splice variants. HDAC6 has a role in regulating the androgen receptor (AR) by modulating heat shock protein 90 (Hsp90) acetylation, which controls the nuclear localization and activation of the AR in androgen-dependent and independent scenarios. With dual-acting AR–HDAC6 inhibitors it should be possible to target patients who don’t respond to enzalutamide. Herein, we describe the design, synthesis and biological evaluation of dual-acting compounds which target AR and are also specific towards HDAC6. Our efforts led to compound 10 which was found to have potent dual activity (HDAC6 IC 50 = 0.0356 μM and AR binding IC 50 = <0.03 μM). Compound 10 was further evaluated for antagonist and other cell-based activities, in vitro stability and pharmacokinetics. [ABSTRACT FROM AUTHOR]

Abstract: Prospective structure based virtual fragment screening methodologies on two GPCR targets namely the dopamine D3 and the histamine H4 receptors with a library of 12,905 fragments were evaluated. Fragments were docked to the X-ray structure and the homology model of the D3 and H4 receptors, respectively. Representative receptor conformations for ensemble docking were obtained from molecular dynamics trajectories. In vitro confirmed hit rates ranged from 16% to 32%. Hits had high ligand efficiency (LE) values in the range of 0.31–0.74 and also acceptable lipophilic efficiency. The X-ray structure, the homology model and structural ensembles were all found suitable for docking based virtual screening of fragments against these GPCRs. However, there was little overlap among different hit sets and methodologies were thus complementary to each other. [Copyright &y& Elsevier]

Highlights: [•] Functional analysis of rare variants in DRD4 was evaluated by in vitro and in silico approaches. [•] Efficiency of dopamine binding reduced significantly in variant DRD4-V194G receptor protein. [•] DRD4-V194G variant could play a potential role in dopamine deficiency disorders. [•] Identification of such critical variants may have implications for lead molecule development. [ABSTRACT FROM AUTHOR]

Abstract: Induced fit molecular docking studies were performed on BMS-806 derivatives reported as small molecule inhibitors of HIV-1 gp120–CD4 binding. Comprehensive study of protein–ligand interactions guided in identification and design of novel symmetrical N,N′-disubstituted urea and thiourea as HIV-1 gp120–CD4 binding inhibitors. These molecules were synthesized in aqueous medium using microwave irradiation. Synthesized molecules were screened for their inhibitory ability by HIV-1 gp120–CD4 capture enzyme-linked immunosorbent assay (ELISA). Designed compounds were found to inhibit HIV-1 gp120–CD4 binding in micromolar (0.013–0.247μM) concentrations. [Copyright &y& Elsevier]