Searching for potential acetylcholinesterase inhibitors: a combined approach of multi-step similarity search, machine learning and molecular dynamics simulations.

Targeting acetylcholinesterase is one of the most important strategies for developing therapeutics against Alzheimer's disease. In this work, we have employed a new approach that combines machine learning models, a multi-step similarity search of the PubChem library and molecular dynamics simulations to investigate potential inhibitors for acetylcholinesterase. Our search strategy has been shown to significantly enrich the set of compounds with strong predicted binding affinity to acetylcholinesterase.

Design, synthesis and biological evaluation of novel quinazoline derivatives as immune checkpoint inhibitors.

In this work, we report 14 novel quinazoline derivatives as immune checkpoint inhibitors, IDO1 and PD-L1. The antitumor screening of synthesized compounds on ovarian cancer cells indicated that compound V-d and V-l showed the most activity with IC values of about 5 μM. Intriguingly, compound V-d emerges as a stand out, triggering cell death through caspase-dependent and caspase-independent manners.

Silver nanoparticles alter the dimerization of Aβ studied by REMD simulations.

The aggregation of amyloid beta (Aβ) peptides is associated with the development of Alzheimer's disease (AD). However, there has been a growing belief that the oligomerization of Aβ species in different environments has a neurotoxic effect on the patient's brain, causing damage. It is necessary to comprehend the compositions of Aβ oligomers in order to develop medications that may effectively inhibit these neurotoxic forms that affect the nervous system of AD patients.

Design, synthesis and evaluation the bioactivities of novel 1,3-dimethyl-6-amino-1H-indazole derivatives as anticancer agents.

Indoleamine 2,3-dioxygenase (IDO1) is a heme-containing enzyme mainly responsible for the metabolism of tryptophan to kynurenine. To date, the IDO1 inhibitors have been developed intensively for the re-activation of the anticancer immune response. In this report, we designed, and synthesized novel 1,3-dimethyl-6-amino indazole derivatives as IDO1 inhibitors based on the structure of IDO1 active site.

Identifying Possible AChE Inhibitors from Drug-like Molecules via Machine Learning and Experimental Studies.

Acetylcholinesterase (AChE) is one of the most important drug targets for Alzheimer's disease (AD) treatment. In this work, a machine learning model was trained to rapidly and accurately screen large chemical databases for the potential inhibitors of AChE. The obtained results were then validated via in vitro enzyme assay.

Searching for AChE inhibitors from natural compounds by using machine learning and atomistic simulations.

Acetylcholinesterase (AChE) is one of the most important drug targets for Alzheimer's disease treatment. In this work, a combined approach involving machine-learning (ML) model and atomistic simulations was established to predict the ligand-binding affinity to AChE of the natural compounds from VIETHERB database. The trained ML model was first utilized to rapidly and accurately screen the natural compound database for potential AChE inhibitors.

Searching and designing potential inhibitors for SARS-CoV-2 Mpro from natural sources using atomistic and deep-learning calculations.

The spread of severe acute respiratory syndrome coronavirus 2 novel coronavirus (SARS-CoV-2) worldwide has caused the coronavirus disease 2019 (COVID-19) pandemic. A hundred million people were infected, resulting in several millions of death worldwide. In order to prevent viral replication, scientists have been aiming to prevent the biological activity of the SARS-CoV-2 main protease (3CL pro or Mpro).

Marine derivatives prevent MUS81 studies.

The winged-helix domain of the methyl methanesulfonate and ultraviolet-sensitive 81 (MUS81) is a potential cancer drug target. In this context, marine fungi compounds were indicated to be able to prevent MUS81 structure via atomistic simulations. Eight compounds such as (), (), (), (), (), (), () and () were indicated that they are able to prevent the conformation of MUS81 via forming a strong binding affinity to the enzyme via perturbation approach.

Design, synthesis and bioevaluation of novel 6-substituted aminoindazole derivatives as anticancer agents.

In the present study, a series of 6-substituted aminoindazole derivatives were designed, synthesized, and evaluated for bio-activities. The compounds were initially designed as indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors based on the structural feature of five IDO1 inhibitors, which are currently on clinical trials, and the important anticancer activity of the indazole scaffold. One of them, compound -(4-fluorobenzyl)-1,3-dimethyl-1-indazol-6-amine (36), exhibited a potent anti-proliferative activity with an IC value of 0.

Emerging Role of Circulating Tumor Cells in Gastric Cancer.

With over 1 million incidence cases and more than 780,000 deaths in 2018, gastric cancer (GC) was ranked as the 5th most common cancer and the 3rd leading cause of cancer deaths worldwide. Though several biomarkers, including carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA19-9), and cancer antigen 72-4 (CA72-4), have been identified, their diagnostic accuracies were modest. Circulating tumor cells (CTCs), cells derived from tumors and present in body fluids, have recently emerged as promising biomarkers, diagnostically and prognostically, of cancers, including GC.

Impact of the Astaxanthin, Betanin, and EGCG Compounds on Small Oligomers of Amyloid Aβ Peptide.

There is experimental evidence that the astaxanthin, betanin, and epigallocatechin-3-gallate (EGCG) compounds slow down the aggregation kinetics and the toxicity of the amyloid-β (Aβ) peptide. How these inhibitors affect the self-assembly at the atomic level remains elusive. To address this issue, we have performed for each ligand atomistic replica exchange molecular dynamic (REMD) simulations in an explicit solvent of the Aβ trimer from the U-shape conformation and MD simulations starting from Aβ dimer and tetramer structures characterized by different intra- and interpeptide conformations.

New Acetohydrazides Incorporating 2-Oxoindoline and 4-Oxoquinazoline: Synthesis and Evaluation of Cytotoxicity and Caspase Activation Activity.

In our search for new small molecules activating procaspase-3, we have designed and synthesized a series of new acetohydrazides incorporating both 2-oxoindoline and 4-oxoquinazoline scaffolds. Biological evaluation showed that a number of these acetohydrazides were comparably or even more cytotoxic against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer) in comparison to PAC-1, a first procaspase-3 activating compound, which was used as a positive control. One of those new compounds, 2-(6-chloro-4-oxoquinazolin-3(4H)-yl)-N'-[(3Z)-5-methyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene]acetohydrazide activated the caspase-3 activity in U937 human lymphoma cells by 5-fold higher than the untreated control.

and determination of glutaminyl cyclase inhibitors.

Alzheimer's disease (AD) is the most common form of neurodegenerative disease currently. It is widely accepted that AD is characterized by the self-assembly of amyloid beta (Aβ) peptides. The human glutaminyl cyclase (hQC) enzyme is characterized by association with Aβ peptide generation.

Novel 3,4-dihydro-4-oxoquinazoline-based acetohydrazides: Design, synthesis and evaluation of antitumor cytotoxicity and caspase activation activity.

In search for novel small molecules with antitumor cytotoxicity via activating procaspase-3, we have designed and synthesized three series of novel (E)-N'-benzylidene-4-oxoquinazolin-3(4H)-yl)acetohydrazides (5a-j, 6a-h, and 7a-h). On the phenyl ring ò the benzylidene part, three different substituents, including 2-OH-4-OCH, 4-OCH, and 4-N(CH), were introduced, respectively. Biological evaluation showed that the acetohydrazides in series 5a-j, in which the phenyl ring of the benzylidene part was substituted by 2-OH-4-OCH substituent, exhibited potent cytotoxicity against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung).

Prediction of AChE-ligand affinity using the umbrella sampling simulation.

Acetylcholinesterase (AChE) is characterized as a key target for designing inhibitors to prevent Alzheimer's disease (AD). The binding free energy of a ligand to the AChE enzyme is a critical factor to screen the potential inhibitor in addition to pharmacokinetics and pharmacology estimation. The biased sampling or umbrella sampling (US) method emerges as a reliable technique to estimate the AChE-inhibitor affinity.

Discovery of Conformationally Restricted Human Glutaminyl Cyclase Inhibitors as Potent Anti-Alzheimer's Agents by Structure-Based Design.

Alzheimer's disease (AD) is an incurable, progressive neurodegenerative disease whose pathogenesis cannot be defined by one single element but consists of various factors; thus, there is a call for alternative approaches to tackle the multifaceted aspects of AD. Among the potential alternative targets, we aim to focus on glutaminyl cyclase (QC), which reduces the toxic pyroform of β-amyloid in the brains of AD patients. On the basis of a putative active conformation of the prototype inhibitor , a series of N-substituted thiourea, urea, and α-substituted amide derivatives were developed.

Structure-activity relationship of leucyladenylate sulfamate analogues as leucyl-tRNA synthetase (LRS)-targeting inhibitors of Mammalian target of rapamycin complex 1 (mTORC1).

Leucyl-tRNA synthetase (LRS) plays an important role in amino acid-dependent mTORC1 signaling, which is known to be associated with cellular metabolism and proliferation. Therefore, LRS-targeting small molecules that can suppress mTORC1 activation may provide an alternative strategy to current anticancer therapy. In this work, we developed a library of leucyladenylate sulfate analogues by extensively modifying three different pharmacophoric regions comprising adenine, ribose and leucine.

(E)-N'-Arylidene-2-(4-oxoquinazolin-4(3H)-yl) acetohydrazides: Synthesis and evaluation of antitumor cytotoxicity and caspase activation activity.

In our search for novel small molecules activating procaspase-3, we have designed and synthesised a series of novel acetohydrazides incorporating quinazolin-4(3H)-ones (5, 6, 7). Biological evaluation revealed eight compounds with significant cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). The most potent compound 5t displayed cytotoxicity up to 5-fold more potent than 5-FU.

N'-[(E)-Arylidene]-2-(2,3-dihydro-3-oxo-4H-1,4-benzoxazin-4-yl)-acetohydrazides: Synthesis and Evaluation of Caspase Activation Activity and Cytotoxicity.

In our search for novel small cytotoxic molecules potentially activating procaspase-3, we have designed and synthesized a series of novel N'-[(E)-arylidene]-2-(2,3-dihydro-3-oxo-4H-1,4-benzoxazin-4-yl)acetohydrazides (5, 6). Biological evaluation revealed that seven compounds, including 5h, 5j, 5k, 5l, 5n, 6a, and 6b, exhibited moderate to strong cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). Among these compounds, two most cytotoxic compounds (5h and 5j) displayed from 3- up to 10-fold higher potency than PAC-1 and 5-FU in three cancer cell lines tested.

Structure-activity relationship investigation of Phe-Arg mimetic region of human glutaminyl cyclase inhibitors.

Glutamyl cyclase (QC) is a promising therapeutic target because of its involvement in the pathogenesis of Alzheimer's disease. In this study, we developed novel QC inhibitors that contain 3-aminoalkyloxy-4-methoxyphenyl and 4-aminoalkyloxyphenyl groups to replace the previously developed pharmacophore. Several potent inhibitors were identified, showing IC values in a low nanomolar range, and were further studied for in vitro toxicity and in vivo activity.

Potent human glutaminyl cyclase inhibitors as potential anti-Alzheimer's agents: Structure-activity relationship study of Arg-mimetic region.

Pyroglutamate-modified amyloid β peptides (pGlu-Aβ) are highly neurotoxic and promote the formation of amyloid plaques. The pGlu-Aβ peptides are generated by glutaminyl cyclase (QC), and recent clinical studies indicate that QC represents an alternative therapeutic target to treat Alzheimer's disease (AD). We have previously developed a series of QC inhibitors with an extended pharmacophoric scaffold, termed the Arg-mimetic D-region.

Discovery of simplified leucyladenylate sulfamates as novel leucyl-tRNA synthetase (LRS)-targeted mammalian target of rapamycin complex 1 (mTORC1) inhibitors.

Leucyl-tRNA synthetase (LRS) has been reported to be a possible mediator of intracellular amino acids signaling to mTORC1. Given that mTORC1 is associated with cell proliferation and tumorigenesis, the LRS-mediated mTORC1 pathway may offer an alternative strategy in anticancer therapy. In this study, we developed a series of simplified analogues of leucyladenylate sulfamate (1) as LRS-targeted mTORC1 inhibitors.