scholarly journals A Practical Perspective: The Effect of Ligand Conformers on the Negative Image-Based Screening

2019 ◽  
Vol 20 (11) ◽  
pp. 2779 ◽  
Author(s):  
Mira Ahinko ◽  
Sami T. Kurkinen ◽  
Sanna P. Niinivehmas ◽  
Olli T. Pentikäinen ◽  
Pekka A. Postila
Keyword(s):  
Drug Targets ◽  
Drug Candidate ◽  
Lead Discovery ◽  
Similarity Comparison ◽  
Negative Image ◽  
Conformer Generation ◽  
Hands On ◽  
Binding Cavity ◽  
Cox 2 ◽  
Rigid Docking

Negative image-based (NIB) screening is a rigid molecular docking methodology that can also be employed in docking rescoring. During the NIB screening, a negative image is generated based on the target protein’s ligand-binding cavity by inverting its shape and electrostatics. The resulting NIB model is a drug-like entity or pseudo-ligand that is compared directly against ligand 3D conformers, as is done with a template compound in the ligand-based screening. This cavity-based rigid docking has been demonstrated to work with genuine drug targets in both benchmark testing and drug candidate/lead discovery. Firstly, the study explores in-depth the applicability of different ligand 3D conformer generation software for acquiring the best NIB screening results using cyclooxygenase-2 (COX-2) as the example system. Secondly, the entire NIB workflow from the protein structure preparation, model build-up, and ligand conformer generation to the similarity comparison is performed for COX-2. Accordingly, hands-on instructions are provided on how to employ the NIB methodology from start to finish, both with the rigid docking and docking rescoring using noncommercial software. The practical aspects of the NIB methodology, especially the effect of ligand conformers, are discussed thoroughly, thus, making the methodology accessible for new users.

scholarly journals Interbase-FRET binding assay for pre-microRNAs

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mattias Bood ◽  
Anna Wypijewska del Nogal ◽  
Jesper R. Nilsson ◽  
Fredrik Edfeldt ◽  
Anders Dahlén ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Drug Targets ◽  
Structural Changes ◽  
Small Sample Size ◽  
Resonance Energy ◽  
Small Sample ◽  
Titration Calorimetry ◽  
Drug Candidate ◽  
Binding Studies ◽  
Aberrant Expression

AbstractThe aberrant expression of microRNAs (miRs) has been linked to several human diseases. A promising approach for targeting these anomalies is the use of small-molecule inhibitors of miR biogenesis. These inhibitors have the potential to (i) dissect miR mechanisms of action, (ii) discover new drug targets, and (iii) function as new therapeutic agents. Here, we designed Förster resonance energy transfer (FRET)-labeled oligoribonucleotides of the precursor of the oncogenic miR-21 (pre-miR-21) and used them together with a set of aminoglycosides to develop an interbase-FRET assay to detect ligand binding to pre-miRs. Our interbase-FRET assay accurately reports structural changes of the RNA oligonucleotide induced by ligand binding. We demonstrate its application in a rapid, qualitative drug candidate screen by assessing the relative binding affinity between 12 aminoglycoside antibiotics and pre-miR-21. Surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) were used to validate our new FRET method, and the accuracy of our FRET assay was shown to be similar to the established techniques. With its advantages over SPR and ITC owing to its high sensitivity, small sample size, straightforward technique and the possibility for high-throughput expansion, we envision that our solution-based method can be applied in pre-miRNA–target binding studies.

scholarly journals A Chemical Rescue Screen Identifies a Plasmodium falciparum Apicoplast Inhibitor Targeting MEP Isoprenoid Precursor Biosynthesis

2014 ◽  
Vol 59 (1) ◽  
pp. 356-364 ◽  
Author(s):  
Wesley Wu ◽  
Zachary Herrera ◽  
Danny Ebert ◽  
Katie Baska ◽  
Seok H. Cho ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Drug ◽  
Drug Targets ◽  
Specific Activity ◽  
Drug Candidate ◽  
Content Type ◽  
Chemical Rescue ◽  
Growth Inhibitory ◽  
Parasite Populations

ABSTRACTThe apicoplast is an essential plastid organelle found inPlasmodiumparasites which contains several clinically validated antimalarial-drug targets. A chemical rescue screen identified MMV-08138 from the “Malaria Box” library of growth-inhibitory antimalarial compounds as having specific activity against the apicoplast. MMV-08138 inhibition of blood-stagePlasmodium falciparumgrowth is stereospecific and potent, with the most active diastereomer demonstrating a 50% effective concentration (EC50) of 110 nM. Whole-genome sequencing of 3 drug-resistant parasite populations from two independent selections revealed E688Q and L244I mutations inP. falciparumIspD, an enzyme in the MEP (methyl-d-erythritol-4-phosphate) isoprenoid precursor biosynthesis pathway in the apicoplast. The active diastereomer of MMV-08138 directly inhibited PfIspD activityin vitrowith a 50% inhibitory concentration (IC50) of 7.0 nM. MMV-08138 is the first PfIspD inhibitor to be identified and, together with heterologously expressed PfIspD, provides the foundation for further development of this promising antimalarial drug candidate lead. Furthermore, this report validates the use of the apicoplast chemical rescue screen coupled with target elucidation as a discovery tool to identify specific apicoplast-targeting compounds with new mechanisms of action.

scholarly journals Experimental Validation of a Fragment Library for Lead Discovery Using SPR Biosensor Technology

2010 ◽  
Vol 16 (1) ◽  
pp. 15-25 ◽  
Author(s):  
Malin Elinder ◽  
Matthis Geitmann ◽  
Thomas Gossas ◽  
Per Källblad ◽  
Johan Winquist ◽  
...  
Keyword(s):  
Surface Plasmon Resonance ◽  
Human Serum Albumin ◽  
Drug Targets ◽  
Experimental Validation ◽  
High Sensitivity ◽  
Lead Discovery ◽  
Experimental Procedure ◽  
Spr Biosensor ◽  
Fragment Library ◽  
Hiv 1

A new fragment library for lead discovery has been designed and experimentally validated for use in surface plasmon resonance (SPR) biosensor-based screening. The 930 compounds in the library were selected from 4.6 million commercially available compounds using a series of physicochemical and medicinal chemistry filters. They were screened against 3 prototypical drug targets: HIV-1 protease, thrombin and carbonic anhydrase, and a nontarget: human serum albumin. Compound solubility was not a problem under the conditions used for screening. The high sensitivity of the sensor surfaces allowed the detection of interactions for 35% to 97% of the fragments, depending on the target protein. None of the fragments was promiscuous (i.e., interacted with a stoichiometry ≥5:1 with all 4 proteins), and only 2 compounds dissociated slowly from all 4 proteins. The use of several targets proved valuable since several compounds would have been disqualified from the library on the grounds of promiscuity if fewer target proteins had been used. The experimental procedure allowed an efficient evaluation and exploration of the new fragment library and confirmed that the new library is suitable for SPR biosensor-based screening.

scholarly journals NICEdrug.ch, a workflow for rational drug design and systems-level analysis of drug metabolism

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Homa MohammadiPeyhani ◽  
Anush Chiappino-Pepe ◽  
Kiandokht Haddadi ◽  
Jasmin Hafner ◽  
Noushin Hadadi ◽  
...  
Keyword(s):  
Drug Targets ◽  
Drug Repurposing ◽  
Rational Drug Design ◽  
Bioactive Molecules ◽  
Lead Discovery ◽  
Minimal Impact ◽  
Practical Applications ◽  
Rational Drug ◽  
Golden Standard ◽  
And Performance

The discovery of a drug requires over a decade of intensive research and financial investments – and still has a high risk of failure. To reduce this burden, we developed the NICEdrug.ch resource, which incorporates 250,000 bioactive molecules, and studied their enzymatic metabolic targets, fate, and toxicity. NICEdrug.ch includes a unique fingerprint that identifies reactive similarities between drug–drug and drug–metabolite pairs. We validated the application, scope, and performance of NICEdrug.ch over similar methods in the field on golden standard datasets describing drugs and metabolites sharing reactivity, drug toxicities, and drug targets. We use NICEdrug.ch to evaluate inhibition and toxicity by the anticancer drug 5-fluorouracil, and suggest avenues to alleviate its side effects. We propose shikimate 3-phosphate for targeting liver-stage malaria with minimal impact on the human host cell. Finally, NICEdrug.ch suggests over 1300 candidate drugs and food molecules to target COVID-19 and explains their inhibitory mechanism for further experimental screening. The NICEdrug.ch database is accessible online to systematically identify the reactivity of small molecules and druggable enzymes with practical applications in lead discovery and drug repurposing.

scholarly journals Saururus chinensis-controlled allergic pulmonary disease through NF-κB/COX-2 and PGE2 pathways

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e10043
Author(s):  
MiKyung Song ◽  
Soon-Young Lee ◽  
Minhee Kim ◽  
Sangwoug Park ◽  
Juyeon Park ◽  
...  
Keyword(s):  
Pulmonary Disease ◽  
Morphological Changes ◽  
Water Extract ◽  
Perennial Herb ◽  
Drug Candidate ◽  
Fine Dust ◽  
Cell Hyperplasia ◽  
Protein Levels ◽  
Saururus Chinensis ◽  
Cox 2

Saururus chinensis is a perennial herb found in the northeastern regions of Asia, including Korea, China, and Japan, and is used in traditional medicine. Studies have identified the four major constituents in Saururus chinensis water extract (LHF618®) as miquelianin (11.75 ± 0.092 mg/g), rutin (1.20 ± 0.008 mg/g), quercitrin (2.38 ± 0.389 mg/g), and quercetin (0.068 ± 0.017 mg/g). Saururus chinensis can improve the symptoms of ovalbumin- or fine dust-induced allergic pulmonary disease by suppressing the effects of WBCs and neutrophils in BALF and IgE in the serum. Saururus chinensis dose-dependently recovered morphological changes such as mucous hyper secretion (from 2.7 ± 0.46 to 0.6 ± 0.65), pulmonary epithelial cell hyperplasia (from 2.4 ± 0.55 to 0.7 ± 0.67), and inflammatory cell infiltration (from 2.3 ± 0.45 to 0.6 ± 0.43), and effectively controlled cDNA levels and protein levels of IL-13. It inhibited NF-κB translocation and COX-2 protein synthesis and suppressed the expression of PGE2. Our results show that Saururus chinensis controlled allergic pulmonary disease via the anti-inflammatory pathways, NF-κB/COX-2 and PGE2. Saururus chinensis may be a promising drug candidate against fine dust-induced allergic pulmonary disease.

scholarly journals AN EXHAUSTIVE REVIEW ON EMERGING DRUG TARGETS OF TUBERCULOSIS WITH SPECIAL EMPHASIS ON CELL WALL SYNTHESIS

2021 ◽  
pp. 1-7
Author(s):  
SNEHAL R THAKAR ◽  
DEEPALI A BANSODE
Keyword(s):  
Cell Wall ◽  
Genetic Information ◽  
Drug Targets ◽  
Drug Candidate ◽  
Drug Resistant ◽  
Mortality And Morbidity ◽  
Mycobacterial Cell ◽  
Causes Of Mortality ◽  
Mycobacterial Cell Wall ◽  
Novel Drug

Tuberculosis (TB) is one of the top 10 causes of mortality and morbidity. Worldwide, yet, it has been over 60 years since a novel drug was introduced in market to treat the disease exclusively. Increased number of drug resistant TB cases has prompted the search for novel potent anti-TB drug. Mycobacterial cell wall has unique structure which provides integrity to the cell. The future development of new potent anti-TB drug targets is associated with the synthesis of various cell wall constituents; the structural and genetic information about mycobacterial cell wall envelope is now available. In the present review, we have focused on prospective drug targets that can be optimum triumph for successful drug candidate.

scholarly journals An Insight of Co-Encapsulation Nigella sativa and Cosmos caudatus Kunth Extracts as Anti-Inflammatory Agent Through In Silico Study

2021 ◽  
Vol 24 (5) ◽  
pp. 152-160
Author(s):  
Nadiyah Zuhroh ◽  
Zubaidah Ningsih ◽  
Anna Safitri
Keyword(s):  
Bioactive Compounds ◽  
In Silico ◽  
Nigella Sativa ◽  
In Vivo Studies ◽  
Drug Candidate ◽  
Active Compounds ◽  
Cosmos Caudatus ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 1

This study analyzes anti-inflammatory activity from extracts of Nigella sativa and Cosmos caudatus Kunth co-encapsulated through in silico molecular docking. The LC-MS results revealed that extracts of N. sativa mostly contained thymoquinone and alpha-hederin, whereas quercetin and kaempferol were the major compounds in C. caudatus K. Nevertheless, the bioactive compounds are usually susceptible to degradation by exposure to light, heat, oxygen, which may limit its biological activity. Therefore, encapsulation is one of the promising techniques to protect bioactive compounds. Ligands were encapsulated with chitosan and sodium tripolyphosphate as wall materials. Cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) as the target enzymes were docked with a combination of these active compounds (non-encapsulated and encapsulated), using the HEX 8.0 program, and visualized using the Discovery studio visualizer software v16.1.0.15350. Interestingly, docking results of the combination of encapsulated ligands showed no interactions to COX-1 but interacted with COX-2. Therefore, co-encapsulation of extracts combinations has been suggested to act as anti-inflammatory agents targeted specifically to the COX-2 enzyme. The total energy of the encapsulated of combination of extract compounds to COX-2 were -1425.88 (mol/cal) for thymoquinone + quercetin; -1435.87 (mol/cal) for thymoquinone + kaempferol; 1175.97 (mol/cal) for quercetin + alpha hederin; -957.74 (mol/cal) for kaempferol + alpha hederin; and -283.3 (mol/cal) for diclofenac sodium, as a control NSAID drug. These suggest that encapsulated active compounds in N. sativa and C. caudatus K. have potency as a drug candidate for the selective NSAIDs category, which can be subjected to further in vitro and in vivo studies.

scholarly journals STRUCTURE-BASED DOCKING STUDIES TOWARD EXPLORING THE POTENTIAL ANTICANCER ACTIVITY OF MORIN AGAINST NON-MELANOMA SKIN CANCER THERAPEUTIC DRUG TARGETS

2018 ◽  
Vol 11 (4) ◽  
pp. 61
Author(s):  
Anjugam C ◽  
Sridevi M ◽  
Gnanendra Ts
Keyword(s):  
Binding Energy ◽  
Anticancer Activity ◽  
Drug Targets ◽  
Docking Studies ◽  
Therapeutic Drug ◽  
Peroxisome Proliferator ◽  
Non Melanoma Skin Cancer ◽  
Cox 2 ◽  
Peroxisome Proliferator Activated Receptors ◽  
In Silico Molecular Docking

 Objective: The purpose of this study is to explore the anticancer activity of morin compound against human cyclooxygenase-2 (COX-2) and peroxisome-proliferator-activated receptors (PPARs) isotypes (PPARα and PPARγ) through in silico molecular docking studies.Methods: The 3D structures of human COX-2 complexed with ibuprofen (PDB ID: 4PH9), PPARα complexed with a synthetic agonist (2S)-2-(4- methoxy-3-{[(pyren-1-yl carbonyl) amino] methyl} benzyl) butanoic acid (PDB ID: 3VI8) and PPARγ complexed indomethacin (PDB ID: 3ADX) were retrieved from protein databank. The cocrystallized sites were considered as binding sites, and the docking with morin compound was performed along with their respective cocrystals for each target and compared their interactions and binding affinities.Results: It is observed that the morin compound exhibited better binding energy of -32.9528 kJ/mol against PPARα followed by COX-2 (binding energy: −18.4311 kJ/mol) and PPARγ (binding energy: −17.4228 kJ/mol) when compared to their cocrystallized ligands.Conclusion: The present study suggests that morin compound might serve as potential alternatives in the prevention of skin cancers by showing better activity against PPARα.

scholarly journals Potential Anti-Proliferative, Anti-Inflammatory and Anti-Viral Components from Sinopodophyllum Hexandrum Explored Using Bio-Affinity Ultrafiltration with Multiple Drug Targets

2021 ◽  
Author(s):  
Huixia Feng ◽  
Guilin Chen ◽  
Yongli Zhang ◽  
Mingquan Guo
Keyword(s):  
Molecular Docking ◽  
Drug Targets ◽  
Multiple Drug ◽  
Inhibitory Effects ◽  
Bioactive Ligands ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Topo Ii ◽  
Sinopodophyllum Hexandrum

Abstract Background: Sinopodophyllum hexandrum (S. hexandrum) is a typical Chinese herbal medicine with numerous components and remarkable pharmacological activities. However, the specific phytochemicals responsible for its anti-proliferative, anti-inflammatory and anti-viral effects remain unexplored.Methods: The integrated analytical strategy combining bio-affinity ultrafiltration with multiple drug targets was developed to rapidly screen and identify bioactive ligands from S. hexandrum. The in vitro anti-proliferative and COX-2 inhibitory assays of bioactive ligands screened were further verified by sulforhodamine B (SRB) cell proliferation and cytotoxicity detection and COX-2 inhibitor screening kits, respectively. Molecular docking analysis was also implemented by the AutoDockTools 1.5.6 software.Results: 10, 7, 9 and 9 phytochemicals were screened out and identified as the potential Topo I, Topo II, COX-2 and ACE2 ligands, respectively. Hereinto, podophyllotoxin and quercetin with higher EF values displayed strong inhibitory effects on A549 and HT-29 cells comparable with etoposide and 5-FU. Furthermore, compared with indomethacin at 0.73 ± 0.07 mM, podophyllotoxin and kaempferol with higher EF values exerted stronger inhibitory effects with IC50 values at 0.36 ± 0.02 mM and 10.49 ± 0.61 mM, respectively. Additionally, the optimal binding sites and mode of action between bioactive ligands and multiple drug targets were determined by molecular docking. Wherein, isorhamnetin showed a stronger affinity to ACE2 with the binding energy of -5.72 kcal/mol and the IC50 value at 63.95 mM, lower than MLN-4760 (-4.27 kcal/mol and 738.62 mM). Conclusions: The integrative strategy combining multiple drug targets and bio-affinity ultrafiltration LC-MS in the present study showed very promising potential for the quick screening and identifying bioactive ligands in S. hexandrum for Topo I, Topo II, COX-2 and ACE2, and some bioactive compounds screened out from this work were verified with other in vitro assays, and even better than those positive drugs of interest. Based on these findings, we then first constructed an interacting network among multi-components and multi-targets. In this way, we showcased a quick and reliable experimental strategy for uncovering the underlying mechanism of the empirical traditional applications of S. hexandrum which could also provide valuable information for better understanding the therapeutic targets and therapeutic ligands of other herbal medicines.

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