scholarly journals Selection of Promising Novel Fragment Sized S. aureus SrtA Noncovalent Inhibitors Based on QSAR and Docking Modeling Studies

Molecules ◽  
2021 ◽  
Vol 26 (24) ◽  
pp. 7677
Author(s):  
Dmitry A. Shulga ◽  
Konstantin V. Kudryavtsev
Keyword(s):  
Experimental Testing ◽  
Covalent Binding ◽  
Docking Studies ◽  
Virtual Library ◽  
Promising Target ◽  
Qsar Models ◽  
New Type ◽  
Further Development ◽  
Nanomolar Range ◽  
Selection Of

Sortase A (SrtA) of Staphylococcus aureus has been identified as a promising target to a new type of antivirulent drugs, and therefore, the design of lead molecules with a low nanomolar range of activity and suitable drug-like properties is important. In this work, we aimed at identifying new fragment-sized starting points to design new noncovalent S. aureus SrtA inhibitors by making use of the dedicated molecular motif, 5-arylpyrrolidine-2-carboxylate, which has been previously shown to be significant for covalent binding SrtA inhibitors. To this end, an in silico approach combining QSAR and molecular docking studies was used. The known SrtA inhibitors from the ChEMBL database with diverse scaffolds were first employed to derive descriptors and interpret their significance and correlation to activity. Then, the classification and regression QSAR models were built, which were used for rough ranking of the virtual library of the synthetically feasible compounds containing the dedicated motif. Additionally, the virtual library compounds were docked into the “activated” model of SrtA (PDB:2KID). The consensus ranking of the virtual library resulted in the most promising structures, which will be subject to further synthesis and experimental testing in order to establish new fragment-like molecules for further development into antivirulent drugs.

Selection of worm species and packing in a new type of biologic reactor for sludge reduction

2014 ◽  
Author(s):  
S.X. Li ◽  
Z.H. Wang ◽  
D.M. Li ◽  
W.W. Duan ◽  
S. Mei ◽  
...  
Keyword(s):  
Sludge Reduction ◽  
New Type ◽  
Selection Of

CRITERIONS FOR THE EFFECTIVENESS OF SOCIALLY IMPORTANT INVESTMENT PROJECTS AND THEIR FORMULAS ADOPTED IN RUSSIAN PRACTICE

2020 ◽  
Vol 2 (8) ◽  
pp. 58-64
Author(s):  
A. F. AGEEVA ◽  
Keyword(s):  
Performance Indicators ◽  
Payback Period ◽  
Internal Rate Of Return ◽  
Investment Projects ◽  
Regulatory Documents ◽  
Project Analysis ◽  
Analytical Work ◽  
Methodological Approaches ◽  
Further Development ◽  
Selection Of

The article analyzes domestic guidelines for assessing the effectiveness of investment projects reflected in the regulatory documentation, both current and invalid. Considered are methodological approaches to calculating key performance indicators of investment projects - net discounted income, internal rate of return, discounted payback period and profitability index. The results of the analysis and recommendations for the further development of national regulatory documents for project analysis and methodological approaches to assessing the effectiveness of socially significant investment projects are presented. The results of the analytical work presented in the article are planned to be used to create a methodology for the selection of socially significant projects for the provision of state support.

Novel Iodinated Hydrazide-hydrazones and their Analogues as Acetyl- and Butyrylcholinesterase Inhibitors

2020 ◽  
Vol 20 (23) ◽  
pp. 2106-2117
Author(s):  
Martin Krátký ◽  
Šárka Štěpánková ◽  
Michaela Brablíková ◽  
Katarína Svrčková ◽  
Markéta Švarcová ◽  
...  
Keyword(s):  
Biological Activities ◽  
Structural Parameters ◽  
Covalent Binding ◽  
Docking Studies ◽  
Potent Inhibition ◽  
Brain Barrier Permeability ◽  
Electric Eel ◽  
Ic50 Values ◽  
Ellman’S Method

Background: Hydrazide-hydrazones have been known as scaffold with various biological activities including inhibition of acetyl- (AChE) and butyrylcholinesterase (BuChE). Cholinesterase inhibitors are mainstays of dementias’ treatment. Objective: Twenty-five iodinated hydrazide-hydrazones and their analogues were designed as potential central AChE and BuChE inhibitors. Methods: Hydrazide-hydrazones were synthesized from 4-substituted benzohydrazides and 2-/4- hydroxy-3,5-diiodobenzaldehydes. The compounds were investigated in vitro for their potency to inhibit AChE from electric eel and BuChE from equine serum using Ellman’s method. We calculated also physicochemical and structural parameters for CNS delivery. Results: The derivatives exhibited a moderate dual inhibition with IC50 values ranging from 15.1-140.5 and 35.5 to 170.5 μmol.L-1 for AChE and BuChE, respectively. Generally, the compounds produced a balanced or more potent inhibition of AChE. N'-[(E)-(4-Hydroxy-3,5-diiodophenyl)methylidene]-4- nitrobenzohydrazide 2k and 4-fluoro-N'-(2-hydroxy-3,5-diiodobenzyl)benzohydrazide 3a were the most potent inhibitors of AChE and BuChE, respectively. Structure-activity relationships were established, and molecular docking studies confirmed interaction with enzymes. Conclusion: Many novel hydrazide-hydrazones showed lower IC50 values than rivastigmine against AChE and some of them were comparable for BuChE to this drug used for the treatment of dementia. They interact with cholinesterases via non-covalent binding into the active site. Based on the BOILEDEgg approach, the majority of the derivatives met the criteria for blood-brain-barrier permeability.

Elaboration of Novel TTK1 Inhibitory Leads via QSAR-Guided Selection of Crystallographic Pharmacophores Followed By In vitro Assay

2020 ◽  
Vol 16 ◽  
Author(s):  
Mahmoud A. Al-Sha'er ◽  
Mutasem O. Taha
Keyword(s):  
Standard Error ◽  
Qsar Model ◽  
Qsar Modeling ◽  
Vitro Assay ◽  
Physicochemical Descriptors ◽  
Qsar Models ◽  
Ic50 Values ◽  
Pharmacophore Hypotheses ◽  
Selection Of

Introduction: Tyrosine threonine kinase (TTK1) is a key regulator of chromosome segregation. TTK targeting received recent concern for the enhancement of possible anticancer therapies. Objective: In this regard we employed our well-known method of QSAR-guided selection of best crystallographic pharmacophore(s) to discover considerable binding interactions that anchore inhibitors into TTK1 binding site. Method:Sixtyone TTK1 crystallographic complexes were used to extract 315 pharmacophore hypotheses. QSAR modeling was subsequently used to choose a single crystallographic pharmacophore that when combined with other physicochemical descriptors elucidates bioactivity discrepancy within a list of 55 miscellaneous inhibitors. Results: The best QSAR model was robust and predictive (r2(55) = 0.75, r2LOO = 0.72 , r2press against external testing list of 12 compounds = 0.67), Standard error of estimate (training set) (S)= 0.63 , Standard error of estimate (testing set)(Stest) = 0.62. The resulting pharmacophore and QSAR models were used to scan the National Cancer Institute (NCI) database for new TTK1 inhibitors. Conclusion: Five hits confirmed significant TTK1 inhibitory profiles with IC50 values ranging between 11.7 and 76.6 micM.

Insilico studies, synthesis and antitubercular activity of some novel quinoline – azitidinone derivatives

2020 ◽  
Vol 16 ◽  
Author(s):  
Trupti. S. Chitre ◽  
Kalyani. D. Asgaonkar ◽  
Amrut B. Vikhe ◽  
Shital M Patil ◽  
Dinesh. R. Garud ◽  
...  
Keyword(s):  
Combinatorial Library ◽  
3D Qsar ◽  
Antitubercular Activity ◽  
Structural Features ◽  
Docking Studies ◽  
Quinoline Derivatives ◽  
Qsar Models ◽  
Molecular Modeling Studies ◽  
Lead Generation ◽  
Mcf 7

Background: Diarylquinolines like Bedaquiline have shown promising antitubercular activity by their action of Mycobacterial ATPase. Objective: The structural features necessary for good antitubercular activity for a series of quinoline derivatives were explored through computational chemistry tools like QSAR and combinatorial library generation. In the current study, 3-Chloro-4-(2-mercaptoquinoline-3-yl)-1-substitutedphenylazitidin-2-one derivatives have been designed and synthesized based on molecular modeling studies as anti-tubercular agents. Method: 2D and 3DQSAR analysis was used to designed compounds having quinoline scaffold. The synthesized compounds were evaluated against active and dormant strains of Mycobacterium tuberculosis (MTB) H37 Ra and Mycobacterium bovis BCG. The compounds were also tested for cytotoxicity against MCF-7, A549 and Panc-1 cell lines using MTT assay. Binding affinity of designed compounds was gauged by molecular docking studies. Results: Statistically significant QSAR models generated by SA-MLR method for 2D QSAR exhibited r2 = 0.852, q2 = 0.811and whereas 3D QSAR with SA-kNN showed q2 = 0.77. The synthesized compounds exhibited MIC in the range of 1.38-14.59(µg/ml) .These compounds showed some crucial interaction with MTB Atpase. Conclusion: The present study has shown some promising results which can be further explored for lead generation.

scholarly journals Novel Selective IDO1 Inhibitors with Isoxazolo[5,4-d]pyrimidin-4(5H)-one Scaffold

2021 ◽  
Vol 14 (3) ◽  
pp. 265
Author(s):  
Ana Dolšak ◽  
Tomaž Bratkovič ◽  
Larisa Mlinarič ◽  
Eva Ogorevc ◽  
Urban Švajger ◽  
...  
Keyword(s):  
Systematic Investigation ◽  
The Novel ◽  
Indoleamine 2,3 Dioxygenase ◽  
Tryptophan Dioxygenase ◽  
Promising Target ◽  
Synthetic Procedure ◽  
Ic50 Values ◽  
Novel Scaffold ◽  
Further Development ◽  
Micromolar Range

Indoleamine 2,3-dioxygenase 1 (IDO1) is a promising target in immunomodulation of several pathological conditions, especially cancers. Here we present the synthesis of a series of IDO1 inhibitors with the novel isoxazolo[5,4-d]pyrimidin-4(5H)-one scaffold. A focused library was prepared using a 6- or 7-step synthetic procedure to allow a systematic investigation of the structure-activity relationships of the described scaffold. Chemistry-driven modifications lead us to the discovery of our best-in-class inhibitors possessing p-trifluoromethyl (23), p-cyclohexyl (32), or p-methoxycarbonyl (20, 39) substituted aniline moieties with IC50 values in the low micromolar range. In addition to hIDO1, compounds were tested for their inhibition of indoleamine 2,3-dioxygenase 2 and tryptophan dioxygenase, and found to be selective for hIDO1. Our results thus demonstrate a successful study on IDO1-selective isoxazolo[5,4-d]pyrimidin-4(5H)-one inhibitors, defining promising chemical probes with a novel scaffold for further development of potent small-molecule immunomodulators.

scholarly journals Development of a Colorimetric Sensor for Autonomous, Networked, Real-Time Application

Sensors ◽  
2020 ◽  
Vol 20 (20) ◽  
pp. 5857
Author(s):  
Brandy J. Johnson ◽  
Anthony P. Malanoski ◽  
Jeffrey S. Erickson
Keyword(s):  
Real Time ◽  
Field Trials ◽  
Wireless Sensor ◽  
Broad Area ◽  
Ongoing Effort ◽  
Environmental Air ◽  
Further Development ◽  
Real Time Application ◽  
Selection Of ◽  
Event Occurrence

This review describes an ongoing effort intended to develop wireless sensor networks for real-time monitoring of airborne targets across a broad area. The goal is to apply the spectrophotometric characteristics of porphyrins and metalloporphyrins in a colorimetric array for detection and discrimination of changes in the chemical composition of environmental air samples. The work includes hardware, software, and firmware design as well as development of algorithms for identification of event occurrence and discrimination of targets. Here, we describe the prototype devices and algorithms related to this effort as well as work directed at selection of indicator arrays for use with the system. Finally, we review the field trials completed with the prototype devices and discuss the outlook for further development.

QSAR Studies to Predict Activity of HSP90 Inhibitors

2021 ◽  
Vol 21 ◽  
Author(s):  
Vaishali M. Patil ◽  
Neeraj Masand ◽  
Satya P. Gupta ◽  
Brian S. J. Blagg
Keyword(s):  
Anticancer Agents ◽  
Heat Shock Protein 90 ◽  
New Drugs ◽  
Signaling Proteins ◽  
Hsp90 Inhibitors ◽  
Oncogenic Signaling ◽  
Qsar Studies ◽  
Sar Studies ◽  
Promising Target ◽  
Qsar Models

: Heat shock protein 90 (HSP90) is a multichaperone complex that mediates the maturation and stability of a variety of oncogenic signaling proteins. HSP90 has emerged as a promising target for the development of anticancer agents. Heterocyclic chemical moieties with HSP90 inhibitory activity were studied continuously during the last decades, and resulting data were applied by medicinal chemists to design and develop new drugs. Their structure-activity relationship (SAR) studies and QSAR models have been derived to assist the current drug development process. The QSAR models are obtained via multiple linear regression (MLR) and non-linear approaches. Interpretation of the reported model highlights the core template required to design novel, potent HSP90 inhibitors to be used as anticancer agents.

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