Molecular Docking and QSAR Studies of Coumarin Derivatives as NMT Inhibitors: Simple Structural Features as Potential Modulators of Antifungal Activity

2020 ◽  
Vol 17 (10) ◽  
pp. 1293-1308 ◽  
Author(s):  
Sapna Jain Dabade ◽  
Dheeraj Mandloi ◽  
Amritlal Bajaj
Keyword(s):  
Hydrogen Bonding ◽  
Molecular Docking ◽  
Amino Acid ◽  
Antifungal Agents ◽  
External Validation ◽  
Binding Pocket ◽  
Amino Acid Residues ◽  
Statistical Parameters ◽  
Van Der Waals Volume ◽  
Qsar Analysis

Background: Treatments of fungal diseases, including Candidiasis, remain not up to scratch in spite of the mounting catalog of synthetic antifungal agents. These have served as the impetus for investigating new antifungal agents based on natural products. Consequently, genetic algorithm-multiple linear regression (GA-MLR) based QSAR (Quantitative Structure-Activity Relationship) studies of coumarin analogues along with molecular docking were carried out. Methods: Coumarin analogues with their MIC values were used to generate the training and test sets of compounds for QSAR models development; the analogues were also docked into the binding pocket of NMT (MyristoylCoA: protein N-myristoyltransferase). Results and Discussion: The statistical parameters for internal and external validation of QSAR analysis (R2 = 0.830, Q2 = 0.758, R2Pred = 0.610 and R2m overall = 0.683 ), Y Randomization, Ridge trace, VIF, tolerance and model criteria of Golbraikh and Tropsha data illustrate the robustness of the best proposed QSAR model. Most of the analogues bind to the electrostatic, hydrophobic clamp and display hydrogen bonding with amino acid residues of NMT. Interestingly, the most active coumarin analogue (MolDock score of -189.257) was docked deeply within the binding pocket of NMT, thereby displaying hydrogen bonding with Tyr107, Leu451, Leu450, Gln226, Cys393 and Leu394 amino acid residues. Conclusion: The combinations of descriptors from various descriptor subsets in QSAR analysis have highlighted the role of atomic properties such as polarizability and atomic van der Waals volume to explain the inhibitory activity. The models and related information may pave the way for important insight into the designing of putative NMT inhibitors for Candida albicans.

GA-SMLR-Based QSAR Modeling and Molecular Docking Studies of Bisamidine Derivatives as NMT Inhibitors

2020 ◽  
Vol 5 (4) ◽  
pp. 1-31
Author(s):  
Sapna Jain Dabade ◽  
Dheeraj Mandloi ◽  
Amritlal V. Bajaj ◽  
Naveen Dhingra
Keyword(s):  
Molecular Docking ◽  
External Validation ◽  
Qsar Model ◽  
Docking Studies ◽  
Qsar Modeling ◽  
Statistical Parameters ◽  
Van Der Waals Volume ◽  
Qsar Analysis ◽  
Hydrogen Bond Interactions

The present investigation deals with a combination of genetic algorithm-stepwise multiple linear regression (GA-SMLR)-based QSAR modeling and molecular docking applied to bisamidine analogues in an attempt to explore their role as novel NMT inhibitors of Candida albicans. In this regard, 43 bisamidine analogues were investigated for the development of mathematical models. The robustness of the proposed QSAR model was not only ascertained through traditionally used internal and external validation statistical parameters (Q2= 0.740, R2 = 0.819, R_Pred^2 = 0.636) but also through various R_(m)^2 metrics proposed by Roy and Mitra. The descriptors recognized in the QSAR analysis have culminated a significant role of atomic van der Waals volume, topology, nature of bond and dipole moment to modulate the antifungal activity of compounds under investigation. The most active compound revealed enhanced binding potency with MolDock score of -183.451 kcal/mol and displayed hydrogen bond interactions with active amino acids Leu177, Thr211, Tyr225, and IIe111 of NMT.

scholarly journals Inhibitory Mechanism of Engeletin Against α-Glucosidase

2021 ◽  
Vol 16 (1) ◽  
pp. 1934578X2098672
Author(s):  
Yunbo Li ◽  
Xiaoling Liu ◽  
Haoyu Zhou ◽  
Bo Li ◽  
Igor Kostiantinovich Mazurenko
Keyword(s):  
Hydrogen Bonding ◽  
Molecular Docking ◽  
Amino Acid ◽  
Fluorescence Quenching ◽  
Fluorescence Spectroscopy ◽  
Inhibitory Concentration ◽  
Amino Acid Residues ◽  
Inhibitory Mechanism ◽  
Hydrophobic Force ◽  
First Time

The inhibitory mechanism of engeletin against α-glucosidase was investigated for the first time by fluorescence spectroscopy and molecular docking. The results showed that engeletin could inhibit α-glucosidase in a noncompetitive inhibition mode with a half-maximal inhibitory concentration value of 48.5 ± 6.0 µg/mL (0.11 ± 0.014 mmol/L). It was found that engeletin could cause static fluorescence quenching of α-glucosidase by forming a complex with α-glucosidase. The thermodynamic parameters indicated that the combination of engeletin and α-glucosidase was driven by hydrophobic force. The molecular docking results confirmed that some amino acid residues of α-glucosidase (Trp391, Arg428, Glu429, Gly566, Trp710, Glu771) could interact with engeletin by hydrogen bonding.

scholarly journals In Silico Prediction, Molecular Docking and Dynamics Studies of Steroidal Alkaloids of Holarrhena pubescens Wall. ex G. Don to Guanylyl Cyclase C: Implications in Designing of Novel Antidiarrheal Therapeutic Strategies

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4147
Author(s):  
Neha Gupta ◽  
Saurav Kumar Choudhary ◽  
Neeta Bhagat ◽  
Muthusamy Karthikeyan ◽  
Archana Chaturvedi
Keyword(s):  
Molecular Docking ◽  
Amino Acid ◽  
Guanylyl Cyclase ◽  
Extracellular Domain ◽  
Enterotoxigenic Escherichia Coli ◽  
Watery Diarrhea ◽  
Guanylyl Cyclase C ◽  
Amino Acid Residues ◽  
Lead Compounds

The binding of heat stable enterotoxin (STa) secreted by enterotoxigenic Escherichia coli (ETEC) to the extracellular domain of guanylyl cyclase c (ECDGC-C) causes activation of a signaling cascade, which ultimately results in watery diarrhea. We carried out this study with the objective of finding ligands that would interfere with the binding of STa on ECDGC-C. With this view in mind, we tested the biological activity of a alkaloid rich fraction of Holarrhena pubescens against ETEC under in vitro conditions. Since this fraction showed significant antibacterial activity against ETEC, we decided to test the screen binding affinity of nine compounds of steroidal alkaloid type from Holarrhena pubescens against extracellular domain (ECD) by molecular docking and identified three compounds with significant binding energy. Molecular dynamics simulations were performed for all the three lead compounds to establish the stability of their interaction with the target protein. Pharmacokinetics and toxicity profiling of these leads demonstrated that they possessed good drug-like properties. Furthermore, the ability of these leads to inhibit the binding of STa to ECD was evaluated. This was first done by identifying amino acid residues of ECDGC-C binding to STa by protein–protein docking. The results were matched with our molecular docking results. We report here that holadysenterine, one of the lead compounds that showed a strong affinity for the amino acid residues on ECDGC-C, also binds to STa. This suggests that holadysenterine has the potential to inhibit binding of STa on ECD and can be considered for future study, involving its validation through in vitro assays and animal model studies.

Design of Dual COX-2 and 5-LOX Inhibitors with Iron-Chelating Properties Using Structure-Based and Ligand-Based Methods

2021 ◽  
Vol 18 ◽  
Author(s):  
Jelena Bošković ◽  
Dušan Ružić ◽  
Olivera Čudina ◽  
Katarina Nikolic ◽  
Vladimir Dobričić
Keyword(s):  
Molecular Docking ◽  
External Validation ◽  
Three Dimensional ◽  
3D Qsar ◽  
Quantitative Structure Activity Relationship ◽  
Docking Studies ◽  
Qsar Analysis ◽  
In Silico Admet ◽  
Cox 2 ◽  
Lox Inhibitors

Background: Inflammation is common pathogenesis of many diseases progression, such as malignancy, cardiovascular and rheumatic diseases. The inhibition of the synthesis of inflammatory mediators by modulation of cyclooxygenase (COX) and lipoxygenase (LOX) pathways provides a challenging strategy for the development of more effective drugs. Objective: The aim of this study was to design dual COX-2 and 5-LOX inhibitors with iron-chelating properties using a combination of ligand-based (three-dimensional quantitative structure-activity relationship (3D-QSAR)) and structure-based (molecular docking) methods. Methods: The 3D-QSAR analysis was applied on a literature dataset consisting of 28 dual COX-2 and 5-LOX inhibitors in Pentacle software. The quality of developed COX-2 and 5-LOX 3D-QSAR models were evaluated by internal and external validation methods. The molecular docking analysis was performed in GOLD software, while selected ADMET properties were predicted in ADMET predictor software. Results: According to the molecular docking studies, the class of sulfohydroxamic acid analogues, previously designed by 3D-QSAR, was clustered as potential dual COX-2 and 5-LOX inhibitors with iron-chelating properties. Based on the 3D-QSAR and molecular docking, 1j, 1g, and 1l were selected as the most promising dual COX-2 and 5-LOX inhibitors. According to the in silico ADMET predictions, all compounds had an ADMET_Risk score less than 7 and a CYP_Risk score lower than 2.5. Designed compounds were not estimated as hERG inhibitors, and 1j had improved intrinsic solubility (8.704) in comparison to the dataset compounds (0.411-7.946). Conclusion: By combining 3D-QSAR and molecular docking, three compounds (1j, 1g, and 1l) are selected as the most promising designed dual COX-2 and 5-LOX inhibitors, for which good activity, as well as favourable ADMET properties and toxicity, are expected.

scholarly journals Probing the origins of human acetylcholinesterase inhibition via QSAR modeling and molecular docking

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e2322 ◽  
Author(s):  
Saw Simeon ◽  
Nuttapat Anuwongcharoen ◽  
Watshara Shoombuatong ◽  
Aijaz Ahmad Malik ◽  
Virapong Prachayasittikul ◽  
...  
Keyword(s):  
Hydrogen Bonding ◽  
Molecular Docking ◽  
Binding Pocket ◽  
Binding Energies ◽  
Acetylcholinesterase Inhibition ◽  
Qsar Modeling ◽  
Qsar Study ◽  
Data Set ◽  
Ache Inhibitors ◽  
Redundant Data

Alzheimer’s disease (AD) is a chronic neurodegenerative disease which leads to the gradual loss of neuronal cells. Several hypotheses for AD exists (e.g., cholinergic, amyloid, tau hypotheses, etc.). As per the cholinergic hypothesis, the deficiency of choline is responsible for AD; therefore, the inhibition of AChE is a lucrative therapeutic strategy for the treatment of AD. Acetylcholinesterase (AChE) is an enzyme that catalyzes the breakdown of the neurotransmitter acetylcholine that is essential for cognition and memory. A large non-redundant data set of 2,570 compounds with reported IC50values against AChE was obtained from ChEMBL and employed in quantitative structure-activity relationship (QSAR) study so as to gain insights on their origin of bioactivity. AChE inhibitors were described by a set of 12 fingerprint descriptors and predictive models were constructed from 100 different data splits using random forest. Generated models affordedR2, ${Q}_{\mathrm{CV }}^{2}$ and ${Q}_{\mathrm{Ext}}^{2}$ values in ranges of 0.66–0.93, 0.55–0.79 and 0.56–0.81 for the training set, 10-fold cross-validated set and external set, respectively. The best model built using the substructure count was selected according to the OECD guidelines and it affordedR2, ${Q}_{\mathrm{CV }}^{2}$ and ${Q}_{\mathrm{Ext}}^{2}$ values of 0.92 ± 0.01, 0.78 ± 0.06 and 0.78 ± 0.05, respectively. Furthermore, Y-scrambling was applied to evaluate the possibility of chance correlation of the predictive model. Subsequently, a thorough analysis of the substructure fingerprint count was conducted to provide informative insights on the inhibitory activity of AChE inhibitors. Moreover, Kennard–Stone sampling of the actives were applied to select 30 diverse compounds for further molecular docking studies in order to gain structural insights on the origin of AChE inhibition. Site-moiety mapping of compounds from the diversity set revealed three binding anchors encompassing both hydrogen bonding and van der Waals interaction. Molecular docking revealed that compounds13,5and28exhibited the lowest binding energies of −12.2, −12.0 and −12.0 kcal/mol, respectively, against human AChE, which is modulated by hydrogen bonding,π–πstacking and hydrophobic interaction inside the binding pocket. These information may be used as guidelines for the design of novel and robust AChE inhibitors.

scholarly journals Molecular Modification of Fluoroquinolone-Biodegrading Enzymes Based on Molecular Docking and Homology Modelling

2019 ◽  
Vol 16 (18) ◽  
pp. 3407 ◽  
Author(s):  
Liu ◽  
Sun ◽  
Cui ◽  
Ding
Keyword(s):  
Molecular Docking ◽  
Amino Acid ◽  
Homology Modelling ◽  
Binding Affinities ◽  
The Novel ◽  
Amino Acid Residues ◽  
Degrading Enzyme ◽  
Degrading Enzymes ◽  
Docking Method ◽  
Degradation Effect

To improve the biodegradation efficiency of fluoroquinolone antibiotics during sewage treatment, fluoroquinolone aerobic, anaerobic and facultative degrading enzymes for fluoroquinolone degradation were modified by molecular docking and homology modelling. First, amino acid residues of the binding sites of degrading enzymes for the target fluoroquinolones ciprofloxacin (CIP), norfloxacin (NOR) and ofloxacin (OFL) were analysed by the molecular docking method. The hydrophobic amino acid residues within 5 Å of the target fluoroquinolone molecules were selected as the modification sites. The hydrophobic amino acid residues at the modified sites were replaced by the hydrophilic amino acid residues, and 150 amino acid sequence modification schemes of the degrading enzymes were designed. Subsequently, a reconstruction scheme of the degrading enzyme amino acid sequence reconstruction scheme was submitted to the SWISS-MODEL server and a selected homology modelling method was used to build a new structure of the degrading enzyme. At the same time, the binding affinities between the novel degrading enzymes and the target fluoroquinolones (represented by the docking scoring function) were evaluated by the molecular docking method. It was found that the novel enzymes can simultaneously improve the binding affinities for the three target fluoroquinolones, and the degradation ability of the six modification schemes was increased by more than 50% at the same time. Among the novel enzymes, the affinity effect of the novel anaerobic enzyme (6-1) with CIP, NOR and OFL was significantly increased, with increases of 129.24%, 165.06% and 169.59%, respectively, followed by the facultative enzyme and aerobic enzyme. In addition, the designed degrading enzymes had certain selectivity for the degradation of the target quinolone. Among the novel enzymes, the binding affinities of the novel anaerobic enzyme (6-3) and CIP, the novel aerobic enzyme (3-6) and NOR, and the novel facultative enzyme (13-6) and OFL were increased by 149.71%, 178.57% and 297.12% respectively. Calculations using the Gaussian09 software revealed that the degradation reaction barrier of the novel degrading enzyme (7-1) and CIP NOR and OFL decreased by 37.65 kcal·mol−1, 6.28 kcal·mol−1 and 6.28 kcal·mol−1, respectively, which would result in efficient degradation of the target fluoroquinolone molecules. By analysing the binding affinity of the degrading enzymes before and after the modification with methanol, it was further speculated that the degradation effect of the modified aerobic degrading enzymes on organic matter was lower than that before the modification, and the increase or decrease in the degradation effect was less than 10%. The mechanism analysis found that the interaction between the modified amino acid residues of the degrading enzymes and the fluoroquinolone molecules increased. The average distance between the amino acid residues and the fluoroquinolone molecules represented a comprehensive affinity effect, and its value was positively correlated with the degradation effect of the novel degrading enzymes.

scholarly journals New Anti SARS-Cov-2 Targets for Quinoline Derivatives Chloroquine and Hydroxychloroquine

2020 ◽  
Vol 21 (16) ◽  
pp. 5856
Author(s):  
Davide Gentile ◽  
Virginia Fuochi ◽  
Antonio Rescifina ◽  
Pio Maria Furneri
Keyword(s):  
Hydrogen Bonding ◽  
Amino Acid ◽  
Hydroxyl Group ◽  
Simulation Methods ◽  
Quinoline Derivatives ◽  
Amino Acid Residues ◽  
Polar Amino Acid ◽  
Health Crisis ◽  
E Protein ◽  
Rapid Spread

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created a severe global health crisis. In this paper, we used docking and simulation methods to identify potential targets and the mechanism of action of chloroquine (CQ) and hydroxychloroquine (HCQ) against SARS-CoV-2. Our results showed that both CQ and HCQ influenced the functionality of the envelope (E) protein, necessary in the maturation processes of the virus, due to interactions that modify the flexibility of the protein structure. Furthermore, CQ and HCQ also influenced the proofreading and capping of viral RNA in SARS-CoV-2, performed by nsp10/nsp14 and nsp10/nsp16. In particular, HCQ demonstrated a better energy binding with the examined targets compared to CQ, probably due to the hydrogen bonding of the hydroxyl group of HCQ with polar amino acid residues.

scholarly journals Structure–function studies of human deoxyhypusine synthase: identification of amino acid residues critical for the binding of spermidine and NAD

2001 ◽  
Vol 355 (3) ◽  
pp. 841-849 ◽  
Author(s):  
Chang Hoon LEE ◽  
Patrick Y. UM ◽  
Myung Hee PARK
Keyword(s):  
Crystal Structure ◽  
Enzyme Activity ◽  
Amino Acid ◽  
Binding Sites ◽  
Binding Pocket ◽  
Complete Loss ◽  
Amino Acid Residues ◽  
Deoxyhypusine Synthase ◽  
Positive Identification ◽  
Insight Into

Deoxyhypusine synthase catalyses the first step in the biosynthesis of hypusine [Nε-(4-amino-2-hydroxybutyl)lysine]. The crystal structure of human deoxyhypusine synthase in complex with NAD revealed four NAD-binding sites per enzyme tetramer, and led to a prediction of the spermidine-binding pocket. We have replaced each of the seven amino acid residues at the predicted spermidine-binding site, and eleven residues that contact NAD, on an individual basis with alanine. Of the amino acid residues at the spermidine site, substitution of Asp-243, Trp-327, His-288, Asp-316 or Glu-323 with alanine caused an almost complete loss of spermidine binding and enzyme activity; only the mutation Tyr-305 → Ala showed partial binding and activity. His-288 → Ala was also deficient in terms of binding NAD. NAD binding was significantly reduced in all of the NAD-site mutant enzymes, except for Glu-137 → Ala, which showed a normal binding of NAD, but was totally lacking in spermidine binding. Of the NAD-site mutant enzymes, Asp-342 → Ala, Asp-313 → Ala and Asp-238 → Ala displayed the lowest binding of NAD. These enzymes and His-288Ala also showed a reduced binding of spermidine, presumably because spermidine binding is dependent on NAD. These findings permit the positive identification of amino acid residues critical for binding of spermidine and NAD, and provide a new insight into the complex molecular interactions involved in the deoxyhypusine synthase reaction.

scholarly journals Screening and Characterizing Tyrosinase Inhibitors from Salvia miltiorrhiza and Carthamus tinctorius by Spectrum-Effect Relationship Analysis and Molecular Docking

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Ya-Li Wang ◽  
Guang Hu ◽  
Qian Zhang ◽  
Yu-Xiu Yang ◽  
Qiao-Qiao Li ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Amino Acid ◽  
Salvia Miltiorrhiza ◽  
Carthamus Tinctorius ◽  
Amino Acid Residues ◽  
Analysis Method ◽  
Effect Relationship ◽  
Relationship Analysis ◽  
Ms Analysis ◽  
Spectrum Effect

Tyrosinase (TYR) is a rate-limiting enzyme in the synthesis of melanin, while direct TYR inhibitors are a class of important clinical antimelanoma drugs. This study established a spectrum-effect relationship analysis method and high-performance liquid chromatography-mass spectrometry (LC-MS) analysis method to screen and identify the active ingredients that inhibited TYR in Salvia miltiorrhiza–Carthamus tinctorius (Danshen–Honghua, DH) herbal pair. Seventeen potential active compounds (peaks) in the extract of DH herbal pair were predicted, and thirteen of them were tentatively identified by LC-MS analysis. Furthermore, TYR inhibitory activities of five pure compounds obtained from the DH herbal pair were validated in the test in which kojic acid served as a positive control drug. Among them, three compounds including protocatechuic aldehyde, hydroxysafflor yellow A, and tanshinone IIA were verified to have high TYR inhibitory activity (IC50 value of 455, 498, and 1214 μM, resp.) and bind to the same amino acid residues in TYR catalytic pocket according to the results of the molecular docking test. However, the other two compounds lithospermic acid and salvianolic acid A had a weak effect on TYR, as they do not combine with the active amino acid residues or act on the active center of TYR. Therefore, the developed methods (spectrum-effect relationship analysis and molecular docking) could be used to effectively screen TYR inhibitors in complex mixtures such as natural products.

scholarly journals Determination of three amino acids causing alteration of proteolytic activities of staphylococcal glutamyl endopeptidases

2009 ◽  
Vol 390 (3) ◽  
Author(s):  
Takayuki K. Nemoto ◽  
Toshio Ono ◽  
Yu Shimoyama ◽  
Shigenobu Kimura ◽  
Yuko Ohara-Nemoto
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Protease Activity ◽  
Binding Pocket ◽  
Catalytic Triad ◽  
Amino Acid Residues ◽  
Proteolytic Activities ◽  
Hydrophobic Amino Acids ◽  
The Difference

Abstract Staphylococcus aureus, Staphylococcus epidermidis, and Staphylococcus warneri secrete glutamyl endopeptidases, designated GluV8, GluSE, and GluSW, respectively. The order of their protease activities is GluSE<GluSW<<GluV8. In the present study, we investigated the mechanism that causes these differences. Expression of chimeric proteins between GluV8 and GluSE revealed that the difference is primarily attributed to amino acid residues 170–195, which define the intrinsic protease activity, and additionally to residues 119–169, which affect the proteolytic sensitivity. Among nine substitutions present in residues 170–195 of the three proteases, the substitutions at positions 185, 188, and 189 were responsible for the changes in their activities, and the combination of W185, V188, and P189, which naturally occurs in GluV8, exerts the highest protease activity. W185 and P189 were indispensable for full activity, but V188 could be replaced by hydrophobic amino acids. These three amino acid residues appear to create a substrate-binding pocket together with the catalytic triad and the N-terminal V1, and therefore define the K m values of the proteases. We also describe a method to produce a chimeric form of GluSE and GluV8 that is resistant to proteolysis, and therefore possesses 4-fold higher activity than the wild-type recombinant GluV8.

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