scholarly journals Combined Ensemble Docking and Machine Learning in Identification of Therapeutic Agents with Potential Inhibitory Effect on Human CES1

Molecules ◽  
2019 ◽  
Vol 24 (15) ◽  
pp. 2747 ◽  
Author(s):  
Eliane Briand ◽  
Ragnar Thomsen ◽  
Kristian Linnet ◽  
Henrik Berg Rasmussen ◽  
Søren Brunak ◽  
...  
Keyword(s):  
Machine Learning ◽  
Drug Interactions ◽  
Scoring Function ◽  
Docking Study ◽  
Inhibitory Effect ◽  
Therapeutic Agents ◽  
Learning Approaches ◽  
Ensemble Docking ◽  
Ic50 Values

The human carboxylesterase 1 (CES1), responsible for the biotransformation of many diverse therapeutic agents, may contribute to the occurrence of adverse drug reactions and therapeutic failure through drug interactions. The present study is designed to address the issue of potential drug interactions resulting from the inhibition of CES1. Based on an ensemble of 10 crystal structures complexed with different ligands and a set of 294 known CES1 ligands, we used docking (Autodock Vina) and machine learning methodologies (LDA, QDA and multilayer perceptron), considering the different energy terms from the scoring function to assess the best combination to enable the identification of CES1 inhibitors. The protocol was then applied on a library of 1114 FDA-approved drugs and eight drugs were selected for in vitro CES1 inhibition. An inhibition effect was observed for diltiazem (IC50 = 13.9 µM). Three others drugs (benztropine, iloprost and treprostinil), exhibited a weak CES1 inhibitory effects with IC50 values of 298.2 µM, 366.8 µM and 391.6 µM respectively. In conclusion, the binding site of CES1 is relatively flexible and can adapt its conformation to different types of ligands. Combining ensemble docking and machine learning approaches improves the prediction of CES1 inhibitors compared to a docking study using only one crystal structure.

Evaluating the Effect of Cinnarizine on Promastigotes and Amastigotes forms of Leishmania major

2020 ◽  
Vol 20 (4) ◽  
pp. 550-555 ◽  
Author(s):  
Lima Asgharpour Sarouey ◽  
Parvaneh Rahimi-Moghaddam ◽  
Fatemeh Tabatabaie ◽  
Khadijeh Khanaliha
Keyword(s):  
Flow Cytometry ◽  
Cutaneous Leishmaniasis ◽  
Leishmania Major ◽  
Inhibitory Effect ◽  
Control Group ◽  
Secondary Infections ◽  
Ic50 Values ◽  
J774 Cells ◽  
Mtt Assays

: As an important global disease, cutaneous leishmaniasis is associated with complications such as secondary infections and atrophic scars. The first line treatment with antimonials is expensive and reported to have serious side effects and enhance resistance development. The main objective of this study was to evaluate the effect of Cinnarizine on standard strains of Leishmania major because of paucity of information on this subject. Methods: In this experimental study, four concentrations of the drug (5, 10, 15 and 20 μg/ml) were added to Leishmania major cultures at 24, 48 and 72 hours intervals. MTT assays were performed to determine parasite viability and drug toxicity. Leishmania major promastigotes were augmented to the in vitro cultured macrophages (J774 cells) and then incubated for 72 hours. Half maximal inhibitory concentration (IC50) was ascertained by counting parasites. The inhibitory effect of the drug was compared with that of Glucantime. Flow-cytometry was performed to investigate apoptosis. Each test was repeated thrice. Results: The IC50 values of Cinnarizine after 72 hours were calculated to be 34.76 μg/ml and 23.73 μg/ml for promastigotes and amastigotes, respectively. The results of MTT assays showed 48 % promastigote viability after 72 hour-exposure to Cinnarizine at 20 μg/ml concentration. Programmed cell death in promastigote- and amastigote-infected macrophages was quantified to be 13.66 % and 98.7 %, respectively. Flow- cytometry analysis indicated that Cinnarizine induced early and late apoptosis in parasites. All treatments produced results which differed significantly from control group (P<0.05). Conclusion: Cinnarizine showed low toxicity with anti-leishmanial and apoptosis effects on both promastigote and intracellular amastigote forms. Therefore, we may suggest further assessment on animal models of this drug as candidates for cutaneous leishmaniasis therapy.

scholarly journals Derivatization of Rosmarinic Acid Enhances its in vitro Antitumor, Antimicrobial and Antiprotozoal Properties

Molecules ◽  
2019 ◽  
Vol 24 (6) ◽  
pp. 1078 ◽  
Author(s):  
Silvia Bittner Fialová ◽  
Martin Kello ◽  
Matúš Čoma ◽  
Lívia Slobodníková ◽  
Eva Drobná ◽  
...  
Keyword(s):  
Rosmarinic Acid ◽  
Antimicrobial Agents ◽  
Biological Activities ◽  
Fold Increase ◽  
Inhibitory Effect ◽  
Phosphonium Salts ◽  
Ros Scavenging ◽  
Ic50 Values ◽  
Quaternary Phosphonium Salts

On its own, rosmarinic acid possesses multiple biological activities such as anti-inflammatory, antimicrobial, cardioprotective and antitumor properties, and these are the consequence of its ROS scavenging and inhibitory effect on inflammation. In this study, two quaternary phosphonium salts of rosmarinic acid were prepared for the purpose of increasing its penetration into biological systems with the aim of improving its antimicrobial, antifungal, antiprotozoal and antitumor activity. The synthetized molecules, the triphenylphosphonium and tricyclohexylphosphonium salts of rosmarinic acid, exhibited significantly stronger inhibitory effects on the growth of HCT116 cells with IC50 values of 7.28 or 8.13 μM in comparison to the initial substance, rosmarinic acid (>300 μM). For the synthesized derivatives, we detected a greater than three-fold increase of activity against Acanthamoeba quina, and a greater than eight-fold increase of activity against A. lugdunensis in comparison to rosmarinic acid. Furthermore, we recorded significantly higher antimicrobial activity of the synthetized derivatives when compared to rosmarinic acid itself. Both synthetized quaternary phosphonium salts of rosmarinic acid appear to be promising antitumor and antimicrobial agents, as well as impressive molecules for further research.

scholarly journals Biological and Computational Studies for Dual Cholinesterases Inhibitory Effect of Zerumbone

Nutrients ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1215 ◽  
Author(s):  
Jayeong Hwang ◽  
Kumju Youn ◽  
Yeongseon Ji ◽  
Seonah Lee ◽  
Gyutae Lim ◽  
...  
Keyword(s):  
Docking Simulation ◽  
Inhibitory Effect ◽  
Potential Effect ◽  
Van Der Waals Interactions ◽  
Inhibitory Effects ◽  
Computational Docking ◽  
In Silico Docking ◽  
Ic50 Values ◽  
Physiological Benefits

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) mediate the degradation of acetylcholine (ACh), a primary neurotransmitter in the brain. Cholinergic deficiency occurs during the progression of Alzheimer’s disease (AD), resulting in widespread cognitive dysfunction and decline. We evaluated the potential effect of a natural cholinesterase inhibitor, zerumbone, using in vitro target enzyme assays, as well as in silico docking and ADMET (absorption, distribution, metabolism, excretion, and toxicity) simulation. Zerumbone showed a predominant cholinesterase inhibitory property with IC50 values of 2.74 ± 0.48 µM and 4.12 ± 0.42 µM for AChE and BChE, respectively; however, the modes of inhibition were different. Computational docking simulation indicated that Van der Waals interactions between zerumbone and both the cholinesterases were the main forces responsible for its inhibitory effects. Furthermore, zerumbone showed the best physicochemical properties for both bioavailability and blood–brain barrier (BBB) permeability. Together, in the present study, zerumbone was clearly identified as a unique dual AChE and BChE inhibitor with high permeability across the BBB, suggesting a strong potential for its physiological benefits and/or pharmacological efficacy in the prevention of AD.

scholarly journals Amidine- and Amidoxime-Substituted Heterocycles: Synthesis, Antiproliferative Evaluations and DNA Binding

Molecules ◽  
2021 ◽  
Vol 26 (22) ◽  
pp. 7060
Author(s):  
Silvija Maračić ◽  
Petra Grbčić ◽  
Suresh Shammugam ◽  
Marijana Radić Stojković ◽  
Krešimir Pavelić ◽  
...  
Keyword(s):  
Binding Mode ◽  
Minor Groove ◽  
Inhibitory Effect ◽  
Ic50 Values ◽  
Dna Backbone ◽  
Potent Growth ◽  
Lung Adenocarcinoma A549 ◽  
Sw620 Cells ◽  
Thermal Melting

The novel 1,2,3-triazolyl-appended N- and O-heterocycles containing amidine 4–11 and amidoxime 12–22 moiety were prepared and evaluated for their antiproliferative activities in vitro. Among the series of amidine-substituted heterocycles, aromatic diamidine 5 and coumarine amidine 11 had the most potent growth-inhibitory effect on cervical carcinoma (HeLa), hepatocellular carcinoma (HepG2) and colorectal adenocarcinoma (SW620), with IC50 values in the nM range. Although compound 5 was toxic to non-tumor HFF cells, compound 11 showed certain selectivity. From the amidoxime series, quinoline amidoximes 18 and 20 showed antiproliferative effects on lung adenocarcinoma (A549), HeLa and SW620 cells emphasizing compound 20 that exhibited no cytostatic effect on normal HFF fibroblasts. Results of CD titrations and thermal melting experiments indicated that compounds 5 and 10 most likely bind inside the minor groove of AT-DNA and intercalate into AU-RNA. Compounds 6, 9 and 11 bind to AT-DNA with mixed binding mode, most probably minor groove binding accompanied with aggregate binding along the DNA backbone.

scholarly journals In vitro Complexation of Olmesartan Medoxomil with Dapagliflozin, Vildagliptin and Metformin

2019 ◽  
Vol 18 (2) ◽  
pp. 271-280 ◽  
Author(s):  
Fahima Aktar ◽  
Md Zakir Sultan ◽  
Mohammad A Rashid
Keyword(s):  
Drug Interactions ◽  
Thermo Gravimetric Analysis ◽  
Olmesartan Medoxomil ◽  
Therapeutic Agents ◽  
Gravimetric Analysis ◽  
Thermochemical Properties ◽  
Scanning Calorimetry ◽  
Thermo Gravimetric ◽  
Ft Ir

Drug-drug interactions have been a serious concern for pharmacokinetics, pharmacodynamics and pharmacological profiles of therapeutic agents. The aim of this study was to carry out interactions of olmesartan medoxomil with dapagliflozin, vildagliptin and metformin, which were confirmed by TLC, HPLC and FT-IR. The newly formed complexes showed characteristic thermochemical properties in differential scanning calorimetry (DSC) and thermo gravimetric analysis (TGA). In TLC, three spots from the three complexes were found to be different from their precursor drugs. In HPLC chromatograms, the Rt (retention time) of the pure olmesartan medoxomil, dapagliflozin, vildagliptin and metformin were found to be different from their respective complexes. The FT-IR spectra obtained for drug-drug interactions were seen to demonstrate new pattern of peaks compared to pure drugs. The DSC and TGA thermograms of olmesartan medoxomil, dapagliflozin, vildagliptin and metformin were also found to be different from their complexes. All these variations from parent compounds indicated the formation of new complexes. Dhaka Univ. J. Pharm. Sci. 18(2): 271-180, 2019 (December)

DESIGN, SYNTHESIS AND EVALUATION OF 6-SUBSTITUTED-4-HYDROXY-1-(2- SUBSTITUTEDACETYL)-3-NITROQUINOLIN-2(1H)-ONES FOR ANTICANCER ACTIVITY

INDIAN DRUGS ◽  
2019 ◽  
Vol 56 (12) ◽  
pp. 20-27
Author(s):  
S. S Bhat ◽  
◽  
S. N. MamleDesai ◽  
V. Narvekar ◽  
S. G Shingade ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Docking Study ◽  
The Other ◽  
Secondary Amines ◽  
Chloroacetyl Chloride ◽  
Design Synthesis ◽  
Mass Spectral ◽  
Ic50 Values ◽  
Substituted 1

The present work deals with the synthesis of a series of 6-substituted-4-hydroxy-1-(2-substitued alicyclicaminoacetyl)-3-nitroquinolin-2(1H)-one {IVa-d (1-3)} derivatives and evaluation of their in vitro anticancer activity. Docking study was carried out using EGFR-tyrosine kinase binding site (PDB ID: 1m17) and revealed encouraging results. The sequence of reactions consists of the initial synthesis of 6-substituted 4-hydroxyquinolin-2(1H)-ones (Ia-d), which were further subjected to nitration reaction to give 6- substituted-4-hydroxy-3-nitroquinolin-2(1H)-one (IIa-d). Condensation of compounds (IIa-d) with chloroacetyl chloride resulted in 6-substituted-1-(2-chloroacetyl)-4-hydroxy-3-nitroquinolin-2(1H)-one(IIIa-d), which was subjected to substitution reaction using various secondary amines to yield the title compounds {IVa-d (1-3)}. All the synthesized compounds were characterized by IR, NMR and mass spectral data.All the derivatives were tested for their in vitro anticancer activity using KB (oral cancer) cell lines. Among the synthesized compounds, compound (IVc-2) was found to be the most cytotoxic as compared to the other synthesized derivatives, with IC50 values of 0.2406μM/mL against KB cell line.

scholarly journals Arylaminopropanone Derivatives as Potential Cholinesterase Inhibitors: Synthesis, Docking Study and Biological Evaluation

Molecules ◽  
2020 ◽  
Vol 25 (7) ◽  
pp. 1751
Author(s):  
Anna Hudcová ◽  
Aleš Kroutil ◽  
Renata Kubínová ◽  
Adriana D. Garro ◽  
Lucas J. Gutierrez ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Quantum Mechanics ◽  
Cholinesterase Inhibitors ◽  
Docking Study ◽  
Biological Evaluation ◽  
Enzyme Assays ◽  
Ic50 Values ◽  
Inhibitory Activities ◽  
Dynamics Simulations

Neurodegenerative diseases in which the decrease of the acetylcholine is observed are growing worldwide. In the present study, a series of new arylaminopropanone derivatives with N-phenylcarbamate moiety (1–16) were prepared as potential acetylcholinesterase and butyrylcholinesterase inhibitors. In vitro enzyme assays were performed; the results are expressed as a percentage of inhibition and the IC50 values. The inhibitory activities were compared with reference drugs galantamine and rivastigmine showing piperidine derivatives (1–3) as the most potent. A possible mechanism of action for these compounds was determined from a molecular modelling study by using combined techniques of docking, molecular dynamics simulations and quantum mechanics calculations.

scholarly journals Screening of Therapeutic Agents for COVID-19 Using Machine Learning and Ensemble Docking Studies

2020 ◽  
Vol 11 (17) ◽  
pp. 7058-7065 ◽  
Author(s):  
Rohit Batra ◽  
Henry Chan ◽  
Ganesh Kamath ◽  
Rampi Ramprasad ◽  
Mathew J. Cherukara ◽  
...  
Keyword(s):  
Machine Learning ◽  
Docking Studies ◽  
Therapeutic Agents ◽  
Ensemble Docking

scholarly journals Combining microfluidics with machine learning algorithms for RBC classification in rare hereditary hemolytic anemia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Valeria Rizzuto ◽  
Arianna Mencattini ◽  
Begoña Álvarez-González ◽  
Davide Di Giuseppe ◽  
Eugenio Martinelli ◽  
...  
Keyword(s):  
Machine Learning ◽  
Hemolytic Anemia ◽  
In Vitro Study ◽  
Clinical Diagnostics ◽  
Video Data ◽  
Machine Learning Algorithms ◽  
Majority Voting ◽  
Learning Approaches ◽  
Behavior Study

AbstractCombining microfluidics technology with machine learning represents an innovative approach to conduct massive quantitative cell behavior study and implement smart decision-making systems in support of clinical diagnostics. The spleen plays a key-role in rare hereditary hemolytic anemia (RHHA), being the organ responsible for the premature removal of defective red blood cells (RBCs). The goal is to adapt the physiological spleen filtering strategy for in vitro study and monitoring of blood diseases through RBCs shape analysis. Then, a microfluidic device mimicking the slits of the spleen red pulp area and video data analysis are combined for the characterization of RBCs in RHHA. This microfluidic unit is designed to evaluate RBC deformability by maintaining them fixed in planar orientation, allowing the visual inspection of RBC’s capacity to restore their original shape after crossing microconstrictions. Then, two cooperative learning approaches are used for the analysis: the majority voting scheme, in which the most voted label for all the cell images is the class assigned to the entire video; and the maximum sum of scores to decide the maximally scored class to assign. The proposed platform shows the capability to discriminate healthy controls and patients with an average efficiency of 91%, but also to distinguish between RHHA subtypes, with an efficiency of 82%.

Sign in / Sign up

Export Citation Format

Share Document