Molecular docking of a series of peptidomimetics in the trypanothione binding site of T. cruzi Trypanothione Reductase

Background:PIM-1 is a kinase which has been related to the oncogenic processes like cell survival, proliferation, and multidrug resistance (MDR). This kinase is known for its ability to phosphorylate the main extrusion pump (ABCB1) related to the MDR phenotype.Objective:In the present work, we tested a new mechanistic insight on the AZD1208 (PIM-1 specific inhibitor) under interaction with chemotherapy agents such as Daunorubicin (DNR) and Vincristine (VCR).Materials and Methods:In order to verify a potential cytotoxic effect based on pharmacological synergism, two MDR cell lines were used: Lucena (resistant to VCR) and FEPS (resistant to DNR), both derived from the K562 non-MDR cell line, by MTT analyses. The activity of Pgp was ascertained by measuring accumulation and the directional flux of Rh123. Furthermore, we performed a molecular docking simulation to delve into the molecular mechanism of PIM-1 alone, and combined with chemotherapeutic agents (VCR and DNR).Results:Our in vitro results have shown that AZD1208 alone decreases cell viability of MDR cells. However, co-exposure of AZD1208 and DNR or VCR reverses this effect. When we analyzed the ABCB1 activity AZD1208 alone was not able to affect the pump extrusion. Differently, co-exposure of AZD1208 and DNR or VCR impaired ABCB1 activity, which could be explained by compensatory expression of abcb1 or other extrusion pumps not analyzed here. Docking analysis showed that AZD1208 is capable of performing hydrophobic interactions with PIM-1 ATP- binding-site residues with stronger interaction-based negative free energy (FEB, kcal/mol) than the ATP itself, mimicking an ATP-competitive inhibitory pattern of interaction. On the same way, VCR and DNR may theoretically interact at the same biophysical environment of AZD1208 and also compete with ATP by the PIM-1 active site. These evidences suggest that AZD1208 may induce pharmacodynamic interaction with VCR and DNR, weakening its cytotoxic potential in the ATP-binding site from PIM-1 observed in the in vitro experiments.Conclusion:Finally, the current results could have a pre-clinical relevance potential in the rational polypharmacology strategies to prevent multiple-drugs resistance in human leukemia cancer therapy.

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3D-QSAR and Molecular Docking Studies of HIV-1 Entry Inhibitors Targeting GP120-CD4 Binding Site

Anti-Infective Agents ◽

10.2174/2211352515666170809151958 ◽

2018 ◽

Vol 15 (2) ◽

Author(s):

Bhumika D. Patel ◽

Nidhi Choksi ◽

Kinjal Patel ◽

Qureshi Gulamnizami

Keyword(s):

Molecular Docking ◽

Binding Site ◽

3D Qsar ◽

Docking Studies ◽

Molecular Docking Studies ◽

Entry Inhibitors ◽

Cd4 Binding Site ◽

Hiv 1

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Study of Endogen Substrates, Drug Substrates and Inhibitors Binding Conformations on MRP4 and Its Variants by Molecular Docking and Molecular Dynamics

Molecules ◽

10.3390/molecules26041051 ◽

2021 ◽

Vol 26 (4) ◽

pp. 1051

Author(s):

Edgardo Becerra ◽

Giovanny Aguilera-Durán ◽

Laura Berumen ◽

Antonio Romo-Mancillas ◽

Guadalupe García-Alcocer

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Binding Energy ◽

Binding Site ◽

Binding Sites ◽

Adenosine Monophosphate ◽

Competitive Inhibitor ◽

Umbrella Sampling ◽

Coarse Grained ◽

Nucleotide Polymorphisms

Multidrug resistance protein-4 (MRP4) belongs to the ABC transporter superfamily and promotes the transport of xenobiotics including drugs. A non-synonymous single nucleotide polymorphisms (nsSNPs) in the ABCC4 gene can promote changes in the structure and function of MRP4. In this work, the interaction of certain endogen substrates, drug substrates, and inhibitors with wild type-MRP4 (WT-MRP4) and its variants G187W and Y556C were studied to determine differences in the intermolecular interactions and affinity related to SNPs using protein threading modeling, molecular docking, all-atom, coarse grained, and umbrella sampling molecular dynamics simulations (AA-MDS and CG-MDS, respectively). The results showed that the three MRP4 structures had significantly different conformations at given sites, leading to differences in the docking scores (DS) and binding sites of three different groups of molecules. Folic acid (FA) had the highest variation in DS on G187W concerning WT-MRP4. WT-MRP4, G187W, Y556C, and FA had different conformations through 25 ns AA-MD. Umbrella sampling simulations indicated that the Y556C-FA complex was the most stable one with or without ATP. In Y556C, the cyclic adenosine monophosphate (cAMP) and ceefourin-1 binding sites are located out of the entrance of the inner cavity, which suggests that both cAMP and ceefourin-1 may not be transported. The binding site for cAMP and ceefourin-1 is quite similar and the affinity (binding energy) of ceefourin-1 to WT-MRP4, G187W, and Y556C is greater than the affinity of cAMP, which may suggest that ceefourin-1 works as a competitive inhibitor. In conclusion, the nsSNPs G187W and Y556C lead to changes in protein conformation, which modifies the ligand binding site, DS, and binding energy.

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Are D-manno-configured Amadori products ligands of the bacterial lectin FimH?

Beilstein Journal of Organic Chemistry ◽

10.3762/bjoc.11.123 ◽

2015 ◽

Vol 11 ◽

pp. 1096-1104 ◽

Cited By ~ 8

Author(s):

Tobias-Elias Gloe ◽

Insa Stamer ◽

Cornelia Hojnik ◽

Tanja M Wrodnigg ◽

Thisbe K Lindhorst

Keyword(s):

Molecular Docking ◽

Binding Site ◽

Bacterial Adhesion ◽

Carbohydrate Binding ◽

Amadori Products ◽

E Coli ◽

Type D ◽

Amadori Rearrangement ◽

Carbohydrate Binding Site

The Amadori rearrangement was employed for the synthesis ofC-glycosyl-type D-mannoside analogues, namely 1-propargylamino- and 1-phenylamino-1-deoxy-α-D-manno-heptopyranose. They were investigated as ligands of type 1-fimbriatedE. colibacteria by means of molecular docking and bacterial adhesion studies. It turns out that Amadori rearrangement products have a limited activity as inhibitors of bacterial adhesion because the β-C-glycosidically linked aglycone considerably hampers complexation within the carbohydrate binding site of the type 1-fimbrial lectin FimH.

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Antifungal Agents: Design, Synthesis, Antifungal Activity and Molecular Docking of Phloroglucinol Derivatives

Molecules ◽

10.3390/molecules23123116 ◽

2018 ◽

Vol 23 (12) ◽

pp. 3116 ◽

Cited By ~ 1

Author(s):

Xingxing Teng ◽

Yuanyuan Wang ◽

Jinhua Gu ◽

Peiqi Shi ◽

Zhibin Shen ◽

...

Keyword(s):

Molecular Docking ◽

Antifungal Activity ◽

Protein Binding ◽

Binding Site ◽

Antifungal Agents ◽

Trichophyton Rubrum ◽

Trichophyton Mentagrophytes ◽

Protein Binding Site ◽

Antifungal Activities ◽

Phloroglucinol Derivatives

Pseudoaspidinol is a phloroglucinol derivative with Antifungal activity and is a major active component of Dryopteris fragrans. In our previous work, we studied the total synthesis of pseudoaspidinol belonging to a phloroglucinol derivative and investigated its antifungal activity as well as its intermediates. However, the results showed these compounds have low antifungal activity. In this study, in order to increase antifungal activities of phloroglucinol derivatives, we introduced antifungal pharmacophore allylamine into the methylphloroglucinol. Meanwhile, we remained C1–C4 acyl group in C-6 position of methylphloroglucinol using pseudoaspidinol as the lead compound to obtain novel phloroglucinol derivatives, synthesized 17 compounds, and evaluated antifungal activities on Trichophyton rubrum and Trichophyton mentagrophytes in vitro. Molecular docking verified their ability to combine the protein binding site. The results indicated that most of the compounds had strong antifungal activity, in which compound 17 were found to be the most active on Trichophyton rubrum with Minimum Inhibitory Concentration (MIC) of 3.05 μg/mL and of Trichophyton mentagrophytes with MIC of 5.13 μg/mL. Docking results showed that compounds had a nice combination with the protein binding site. These researches could lay the foundation for developing antifungal agents of clinical value.

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Cellulase enzyme: Homology modeling, binding site identification and molecular docking

Journal of Molecular Structure ◽

10.1016/j.molstruc.2017.08.067 ◽

2017 ◽

Vol 1150 ◽

pp. 61-67 ◽

Cited By ~ 9

Author(s):

K. Selvam ◽

D. Senbagam ◽

T. Selvankumar ◽

C. Sudhakar ◽

S. Kamala-Kannan ◽

...

Keyword(s):

Molecular Docking ◽

Homology Modeling ◽

Binding Site ◽

Cellulase Enzyme ◽

Binding Site Identification ◽

Site Identification

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A molecular dynamics simulation study of the ACE2 receptor with screened natural inhibitors to identify novel drug candidate against COVID-19

PeerJ ◽

10.7717/peerj.11171 ◽

2021 ◽

Vol 9 ◽

pp. e11171

Author(s):

Neha Srivastava ◽

Prekshi Garg ◽

Prachi Srivastava ◽

Prahlad Kishore Seth

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Molecular Dynamics Simulation ◽

Binding Site ◽

Cinnamic Acid ◽

Simulation Study ◽

Computational Study ◽

Dynamics Simulation ◽

Receptor Protein ◽

Novel Therapeutic

Background & Objectives The massive outbreak of Novel Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) has turned out to be a serious global health issue worldwide. Currently, no drugs or vaccines are available for the treatment of COVID-19. The current computational study was attempted to identify a novel therapeutic inhibitor against novel SARS-CoV-2 using in silico drug discovery pipeline. Methods In the present study, the human angiotensin-converting enzyme 2 (ACE2) receptor was the target for the designing of drugs against the deadly virus. The 3D structure of the receptor was modeled & validated using a Swiss-model, Procheck & Errat server. A molecular docking study was performed between a group of natural & synthetic compounds having proven anti-viral activity with ACE2 receptor using Autodock tool 1.5.6. The molecular dynamics simulation study was performed using Desmond v 12 to evaluate the stability and interaction of the ACE2 receptor with a ligand. Results Based on the lowest binding energy, confirmation, and H-bond interaction, cinnamic acid (−5.20 kcal/mol), thymoquinone (−4.71 kcal/mol), and andrographolide (Kalmegh) (−4.00 kcal/mol) were screened out showing strong binding affinity to the active site of ACE2 receptor. MD simulations suggest that cinnamic acid, thymoquinone, and andrographolide (Kalmegh) could efficiently activate the biological pathway without changing the conformation in the binding site of the ACE2 receptor. The bioactivity and drug-likeness properties of compounds show their better pharmacological property and safer to use. Interpretation & Conclusions The study concludes the high potential of cinnamic acid, thymoquinone, and andrographolide against the SARS-CoV-2 ACE2 receptor protein. Thus, the molecular docking and MD simulation study will aid in understanding the molecular interaction between ligand and receptor binding site, thereby leading to novel therapeutic intervention.

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In-silico Investigation of the Interaction between Beta-class Glutathione S-Transferase and Five Antibiotics, namely; Ampicillin, Tetracycline, Chloramphenicol, Ciprofloxacin and Cephalexin

Journal of Applied Sciences and Environmental Management ◽

10.4314/jasem.v25i4.2 ◽

2021 ◽

Vol 25 (4) ◽

pp. 497-502

Author(s):

D. Shehu ◽

S Danlami ◽

M. Ya’u ◽

A. Babandi ◽

H.M. Yakasai ◽

...

Keyword(s):

Amino Acids ◽

Antibiotic Resistance ◽

Molecular Docking ◽

Binding Site ◽

Substrate Binding ◽

Docking Study ◽

Glutathione S Transferase ◽

Molecular Docking Study ◽

Substrate Binding Site ◽

Glutathione S Transferases

Glutathione s-transferases(GSTs) are enzymes involved in the conjugation and deactivation of various xenobiotics including drugs. Thisin-silico study was undertaken in order to investigate the interaction between beta-class glutathione s-transferase and five selected antibiotics, namely; ampicillin, tetracycline, chloramphenicol, ciprofloxacin and cephalexin using molecular docking study. RaptorX server was used to predict the amino acids involved at the binding sitewhile molecular docking study was employed in order to investigate the binding interactions.RaptorX predicted several amino acids which were different from the ones observed in molecular docking because of the variability in the substrate binding site of GSTs however, all the amino acids predicted by RaptorX were also found to be involved in the GSH binding.Lys107, Phe109, Ser110, Leu113, Trp114, His115 and Arg123, Leu168 were the amino acids involved in the binding of various antibiotics to the substrate binding site of the protein while Ala9, Cys10, Leu32, Tyr51, Val52, Pro53, Glu65 and Ala66were involved in the binding of the co-substrate GSH to the binding site of the protein. The results indicated that all the antibiotics showed a good binding affinity with the beta class GST and are therefore capable of deactivating the drugs. With these, finding a beta class GST inhibitors alongside antibiotics during a treatment of diseases will be of beneficial in the current fight against antibiotic resistance.

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Molecular docking of four β-amyloid1–42 fragments on the α7 nicotinic receptor: delineating the binding site of the Aβ peptides

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2004.08.218 ◽

2004 ◽

Vol 323 (4) ◽

pp. 1191-1196 ◽

Cited By ~ 7

Author(s):

L. Michel Espinoza-Fonseca

Keyword(s):

Molecular Docking ◽

Binding Site ◽

Nicotinic Receptor ◽

Aβ Peptides

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Identification of Small Molecule Inhibitors of the Deubiquitinating Activity of the SARS-CoV-2 Papain-Like Protease: in silico Molecular Docking Studies and in vitro Enzymatic Activity Assay

Frontiers in Chemistry ◽

10.3389/fchem.2020.623971 ◽

2020 ◽

Vol 8 ◽

Author(s):

Eleni Pitsillou ◽

Julia Liang ◽

Katherine Ververis ◽

Kah Wai Lim ◽

Andrew Hung ◽

...

Keyword(s):

Molecular Docking ◽

Enzymatic Activity ◽

Small Molecules ◽

Binding Site ◽

Protein Docking ◽

Activity Assay ◽

Epicatechin Gallate ◽

Inhibitor Binding ◽

Enzymatic Activity Assay

COVID-19 is an ongoing pandemic caused by the SARS-CoV-2 virus with important political, socio-economic, and public health consequences. Inhibiting replication represents an important antiviral approach, and in this context two viral proteases, the SARS-CoV-2 main and papain-like proteases (PLpro), which cleave pp1a and pp1ab polypeptides, are critical. Along with protease activity, the PLpro possesses deubiquitinating activity, which is important in immune regulation. Naphthalene-based inhibitors, such as the well-investigated GRL-0617 compound, have been shown to possess dual effects, inhibiting both protease and deubiquitinating activity of the PLpro. Rather than binding to the canonical catalytic triad, these type of non-covalent inhibitors target an adjacent pocket, the naphthalene-inhibitor binding site. Using a high-throughput screen, we have previously identified the dietary hypericin, rutin, and cyanidin-3-O-glucoside compounds as potential protease inhibitors targeting the naphthalene-inhibitor binding site. Here, our aim was to investigate the binding characteristics of these compounds to the PLpro, and to evaluate deubiquitinating activity, by analyzing seven different PLpro crystal structures. Molecular docking highlighted the relatively high affinity of GRL-0617 and dietary compounds. In contrast binding of the small molecules was abolished in the presence of ubiquitin in the palm subdomain of the PLpro. Further, docking the small molecules in the naphthalene-inhibitor binding site, followed by protein-protein docking revealed displacement of ubiquitin in a conformation inconsistent with functional activity. Finally, the deubiquitinating activity was validated in vitro using an enzymatic activity assay. The findings indicated that the dietary compounds inhibited deubiquitinase activity in the micromolar range with an order of activity of GRL-0167, hypericin >> rutin, cyanidin-3-O-glucoside > epigallocatechin gallate, epicatechin gallate, and cefotaxime. Our findings are in accordance with mechanisms and potential antiviral effects of the naphthalene-based, GRL-0617 inhibitor, which is currently progressing in preclinical trials. Further, our findings indicate that in particular hypericin, rutin, and cyanidin-3-O-glucoside, represent suitable candidates for subsequent evaluation as PLpro inhibitors.

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