Computational Investigations on Reaction Mechanisms of the Covalent Inhibitors Ponatinib and Analogs Targeting the Extracellular Signal-Regulated Kinases.

As an important cancer therapeutic target, extracellular signal-regulated kinases (ERK) are involved in triggering various cellular responses in tumors. Regulation of the ERK signaling pathway by the small molecular inhibitors is highly desired for the sake of cancer therapy. In contrast to the routine inhibitors targeting ERKs through long-range non-bonding interactions, Ponatinib, a covalent inhibitor to ERK2 with a macrocyclic structure characterized by the α,β-C=C unsaturated ketone, can form the stable -C(S)-C(H)-type complex via the four-center barrier due to the nucleophilic addition reaction of the thiol group of the Cys166 residue of ERK2 with the C=C double bond of Ponatinib with reaction free-energy barrier of 47.

Pharmacophore-based virtual screening, molecular docking and molecular dynamics simulation for identification of potential ERK inhibitors.

As the downstream component of the mitogen-activated protein kinases (MAPK) pathway, the extracellular signal-regulated kinase (ERK) is responsible for phosphorylating a broad range of substrates in cell proliferation, differentiation, and survival. Direct targeting the ERK proteins by the piperidinopyrimidine urea-based inhibitors has been demonstrated to be an effective way to block the MAPK signaling pathway in inhibiting tumor growth. In order to discover better inhibitors, a computer-aided drug design (CADD) approach was employed to reveal the pharmacological characteristics and mechanisms of action.

Two-Dimensional Ultrasound and Triplane Tissue Doppler Ultrasound of Patients with Severe Preeclampsia.

This study was to investigate the cardiac function characteristics under two-dimensional ultrasound and triplane tissue Doppler imaging (TDI) of patients with severe preeclampsia (SPE). 28 SPE patients with singleton pregnancy from January 2018 to December 2020 were included in the SPE group. 25 healthy nonpregnant women of reproductive age were taken as the control group (Ctrl group), and 26 normal pregnant women with singleton pregnancy were selected as the normal group (Norm group); all the research objects underwent ultrasonography.

Design of Novel HIV-1 NNRTIs Based on Combined Modeling Studies of Dihydrofuro[3,4-d]pyrimidines.

A novel series of dihydrofuro[3,4-d]pyrimidine (DHPY) analogs have recently been recognized as promising HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) with potent antiviral activity. To better understand the pharmacological essentiality of these DHPYs and design novel NNRTI leads, in this work, a systematic study was performed on 52 DHPYs using three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, virtual screening, absorption-distribution-metabolism-excretion (ADME) prediction, and molecular dynamics (MD) methods. The generated 3D-QSAR models exhibited satisfactory parameters of internal validation and well-externally predictive capacity, for instance, the q, R, and of the optimal comparative molecular similarity indices analysis model were 0.

A NMR-based drug screening strategy for discovering active substances from herbal medicines: Using Radix Polygoni Multiflori as example.

Ethnopharmacological Relevance: Herbal medicines have always been important sources for new drugs. And developing new drugs from traditional herbal medicine is currently still an effective way. However, screening for active substances from herbal medicines extracts has ever been a challenging topic, due to their intrinsic complexity.

Identification of The Fipronil Resistance Associated Mutations in GABA Receptors by Molecular Modeling.

Fipronil, as the first commercialized member of phenylpyrazole insecticides, has been widely used to control planthoppers in China due to its high insecticidal activity and low toxicity to mammals. However, insects have developed resistance to phenylpyrazoles after their long-term use. The resistance mechanism of insects to fipronil has not been well identified, which limited the development of phenylpyrazole insecticides.

studies of diarylpyridine derivatives as novel HIV-1 NNRTIs using docking-based 3D-QSAR, molecular dynamics, and pharmacophore modeling approaches.

A series of novel diarylpyridine derivatives has recently been identified as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), and most of them exhibited potent activities against HIV-1 strains, with EC values in the low nanomolar range. However, the three-dimensional quantitative structure-activity relationships (3D-QSARs) and pharmacophore characteristics of these compounds remain to be studied. In the present study, forty-two diarylpyridine derivatives were firstly docked into HIV-1 reverse transcriptase, and molecular dynamics (10 ns) simulations were further performed to validate the reliability of the docking results, which indicated that residues Lys101, Tyr181, Tyr188, Phe227, and Trp229 might play important roles in binding with these diarylpyridines.