scholarly journals Structure-Based Virtual Screening Identifies Multiple Stable Binding Sites at the RecA Domains of SARS-CoV-2 Helicase Enzyme

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1446
Author(s):  
Sajjad Ahmad ◽  
Yasir Waheed ◽  
Saba Ismail ◽  
Saadia Bhatti ◽  
Sumra Wajid Abbasi ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Binding Site ◽  
Binding Affinity ◽  
Binding Sites ◽  
Simulation Analysis ◽  
Binding Free Energy ◽  
Docking Simulation ◽  
Critical Approach ◽  
Screening Process ◽  
Atp Binding Site

With the emergence and global spread of the COVID-19 pandemic, the scientific community worldwide has focused on search for new therapeutic strategies against this disease. One such critical approach is targeting proteins such as helicases that regulate most of the SARS-CoV-2 RNA metabolism. The purpose of the current study was to predict a library of phytochemicals derived from diverse plant families with high binding affinity to SARS-CoV-2 helicase (Nsp13) enzyme. High throughput virtual screening of the Medicinal Plant Database for Drug Design (MPD3) database was performed on SARS-CoV-2 helicase using AutoDock Vina. Nilotinib, with a docking value of −9.6 kcal/mol, was chosen as a reference molecule. A compound (PubChem CID: 110143421, ZINC database ID: ZINC257223845, eMolecules: 43290531) was screened as the best binder (binding energy of −10.2 kcal/mol on average) to the enzyme by using repeated docking runs in the screening process. On inspection, the compound was disclosed to show different binding sites of the triangular pockets collectively formed by Rec1A, Rec2A, and 1B domains and a stalk domain at the base. The molecule is often bound to the ATP binding site (referred to as binding site 2) of the helicase enzyme. The compound was further discovered to fulfill drug-likeness and lead-likeness criteria, have good physicochemical and pharmacokinetics properties, and to be non-toxic. Molecular dynamic simulation analysis of the control/lead compound complexes demonstrated the formation of stable complexes with good intermolecular binding affinity. Lastly, affirmation of the docking simulation studies was accomplished by estimating the binding free energy by MMPB/GBSA technique. Taken together, these findings present further in silco investigation of plant-derived lead compounds to effectively address COVID-19.

scholarly journals In Silico Exploration of Phytoconstituents From Phyllanthus emblica and Aegle marmelos as Potential Therapeutics Against SARS-CoV-2 RdRp

2021 ◽  
Vol 15 ◽  
pp. 117793222110274
Author(s):  
Khushboo Pandey ◽  
Kiran Bharat Lokhande ◽  
K Venkateswara Swamy ◽  
Shuchi Nagar ◽  
Manjusha Dake
Keyword(s):  
Molecular Docking ◽  
Binding Affinity ◽  
Simulation Analysis ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Molecular Field ◽  
Hydroxyl Groups ◽  
Phyllanthus Emblica ◽  
Inhibitory Potential ◽  
Novel Drug

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide has increased the importance of computational tools to design a drug or vaccine in reduced time with minimum risk. Earlier studies have emphasized the important role of RNA-dependent RNA polymerase (RdRp) in SARS-CoV-2 replication as a potential drug target. In our study, comprehensive computational approaches were applied to identify potential compounds targeting RdRp of SARS-CoV-2. To study the binding affinity and stability of the phytocompounds from Phyllanthus emblica and Aegel marmelos within the defined binding site of SARS-CoV-2 RdRp, they were subjected to molecular docking, 100 ns molecular dynamics (MD) simulation followed by post-simulation analysis. Furthermore, to assess the importance of features involved in the strong binding affinity, molecular field-based similarity analysis was performed. Based on comparative molecular docking and simulation studies of the selected phytocompounds with SARS-CoV-2 RdRp revealed that EBDGp possesses a stronger binding affinity (−23.32 kcal/mol) and stability than other phytocompounds and reference compound, Remdesivir (−19.36 kcal/mol). Molecular field-based similarity profiling has supported our study in the validation of the importance of the presence of hydroxyl groups in EBDGp, involved in increasing its binding affinity toward SARS-CoV-2 RdRp. Molecular docking and dynamic simulation results confirmed that EBDGp has better inhibitory potential than Remdesivir and can be an effective novel drug for SARS-CoV-2 RdRp. Furthermore, binding free energy calculations confirmed the higher stability of the SARS-CoV-2 RdRp-EBDGp complex. These results suggest that the EBDGp compound may emerge as a promising drug against SARS-CoV-2 and hence requires further experimental validation.

scholarly journals A Variable Domain near the ATP-Binding Site in Drosophila Muscle Myosin Is Part of the Communication Pathway between the Nucleotide and Actin-binding Sites

2007 ◽  
Vol 368 (4) ◽  
pp. 1051-1066 ◽  
Author(s):  
Becky M. Miller ◽  
Marieke J. Bloemink ◽  
Miklós Nyitrai ◽  
Sanford I. Bernstein ◽  
Michael A. Geeves
Keyword(s):  
Binding Site ◽  
Binding Sites ◽  
Variable Domain ◽  
Actin Binding ◽  
Atp Binding ◽  
Atp Binding Site ◽  
Communication Pathway ◽  
Muscle Myosin

scholarly journals In silico exploration of phytoconstituents from Phyllanthus emblica and Aegle marmelos as potential therapeutics against SARS-CoV-2 RdRp

2021 ◽  
Author(s):  
Khushboo Pandey ◽  
Kiran Bharat Lokhande ◽  
K. venkateswara Swamy ◽  
Shuchi Nagar ◽  
Manjusha Dake
Keyword(s):  
Molecular Docking ◽  
Binding Affinity ◽  
Simulation Analysis ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Molecular Field ◽  
Hydroxyl Groups ◽  
Phyllanthus Emblica ◽  
Inhibitory Potential ◽  
Novel Drug

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide has increased the importance of computational tools to design a drug or vaccine in reduced time with minimum risk. Earlier studies have emphasized the important role of RNA-dependent RNA polymerase (RdRp) in SARS-CoV-2 replication as a potential drug target. In our study, comprehensive computational approaches were applied to identify potential compounds targeting RdRp of SARS-CoV-2. To study the binding affinity and stability of the phytocompounds from Phyllanthus emblica and Aegel marmelos within the defined binding site of SARS-CoV-2 RdRp, they were subjected to molecular docking, 100ns molecular dynamics (MD) simulation followed by post-simulation analysis. Further, to assess the importance of features involved in the strong binding affinity, molecular field-based similarity analysis was performed. Based on comparative molecular docking and simulation studies of the selected phytocompounds with SARS-CoV-2 RdRp revealed that, EBDGp possess stronger binding affinity (-23.32 kcal/mol) and stability than other phytocompounds and reference compound, Remdesivir (-19.36 kcal/mol). Molecular field-based similarity profiling has supported our study in the validation of the importance of the presence of hydroxyl groups in EBDGp, involved in increasing its binding affinity towards SARS-CoV-2 RdRp. Molecular docking and dynamic simulation results confirmed that EBDGp has better inhibitory potential than Remdesivir and can be an effective novel drug for SARS-CoV-2 RdRp. Furthermore, binding free energy calculations confirmed the higher stability of the SARS-CoV-2 RdRp-EBDGp complex. These results suggest that the EBDGp compound may emerge as a promising drug against SARS-CoV-2 and hence requires further experimental validation.

scholarly journals VIRTUAL SCREENING AND MOLECULAR DYNAMICS SIMULATION OF COMPOUNDS FROM THE HERBAL DATABASE OF INDONESIA AGAINST HISTONE DEACETYLASE 2

2018 ◽  
Vol 10 (1) ◽  
pp. 235
Author(s):  
Muhammad Teguh Setiawan ◽  
Arry Yanuar
Keyword(s):  
Molecular Dynamics ◽  
Virtual Screening ◽  
Molecular Dynamics Simulations ◽  
Histone Deacetylase ◽  
Simulation Analysis ◽  
Positive Control ◽  
Dynamics Simulation ◽  
Screening Process ◽  
Histone Deacetylase 2 ◽  
Dynamics Simulations

Objective: This study aimed to find the herbal compounds from the database of Indonesian herbs with potential for use as histone deacetylase 2 (HDAC2)enzyme inhibitors through virtual screening using the LigandScout program.Methods: Virtual screening was conducted using LigandScout 4.09.3, AutodockZN, and AutoDockTools.Results: The virtual screening process resulted in 10 compounds with the highest pharmacophore fit score rating, from which five compounds withthe best criteria for molecular dynamics simulations were selected: Boesenbergin B, pongachalcone I, 6,8-diprenylgenistein, marmin, and mangostin.The ΔG values obtained were, respectively, −8.28, −9.15, −7.05, −9.07, and −7.15. The active crystal ligand N-(2-aminophenyl) benzamide was used asa positive control, with ΔG value of −10.27. Molecular dynamic’s simulations showed that the activity of HDAC2 inhibitors was known to interact inthe amino acid residues His145C, Tyr308C, Zn379C, Leu276C, Phe155C, Phe210C, Leu144C, and Met35C.Conclusions: Based on virtual screening and the molecular dynamics simulations, marmin was considered to provide the best overall activity ofanalysis. Simulation analysis of molecular dynamics from hits compound showed that analysis with MMGBSA gave higher free energy binding valuethan MMPBSA.

Abstract P622: Characterization of 125-I-Angiotensin (1-7) Binding to Rat Kidney

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Filipe F Conti ◽  
Andrea Linares ◽  
Leena E Couling ◽  
Mariana Morris ◽  
Katia De Angelis ◽  
...  
Keyword(s):  
Binding Site ◽  
Binding Affinity ◽  
Binding Sites ◽  
Specific Activity ◽  
Specific Binding ◽  
Rat Kidney ◽  
Albino Rats ◽  
Angiotensin Peptides ◽  
Putative Receptor ◽  
Wet Weight

Despite the plethora of data indicating beneficial effects of angiotensin (1-7) (Ang 1-7) on the cardiovascular system, its putative receptor, Mas, has not been characterized in tissue membrane preparations other than single concentration demonstrations of the localization of 125 I-Ang 1-7 binding sites in rat kidney. This does not indicate the specificity of 125 I-Ang 1-7 binding nor does it indicate the actual densities of the binding sites, i.e., B max (fmoles/mg tissue), or dissociation constant (K D ) to indicate binding affinity of 125 I-Ang 1-7 for its putative receptor. To characterize 125 I-Ang 1-7 binding in the kidney we prepared a low specific activity, monoradioiodinated Ang 1-7 using a 1:19 mix of 125 iodine : 127 iodine which allows for assessment of the B max and K D with concentrations of radioligand up to 100 nM. Frozen kidneys from adult male albino rats were dissected and homogenized in water and the membranes were precipitated by centrifugation at 48 kxG. Membranes were resuspended in Tris:MgCl 2 (50:1) pH 7.2 and incubated with 12 concentrations of 125/127 I-Ang 1-7 ranging from ~3-100 nM for 30 min at 22 C, after which bound 125/127 I-Ang 1-7 was resolved from unbound 125/127 I-Ang 1-7 by filtration and measured with a gamma counter. Specific binding (defined as 100 μM Ang 1-7 displaceable binding) of 125/127 I-Ang 1-7 showed a moderate binding affinity (K D = 14.7 ± 1.8 nM) and binding site density (B max = 24.5 ± 9.9 fmoles/mg initial wet weight). The B max value tended to be lower than that in the liver (B max = 62.3 ± 20.1 fmoles/mg initial wet weight) and the K D value was significantly greater (lower affinity) than that in the liver ( K D = 5.7 ± 0.6 nM, p = 0.0085). Of note, competition for 125/127 I-Ang 1-7 binding Ang 1-7 indicated that the IC 50 for Ang 1-7 competition for 125/127 I-Ang 1-7 binding was 42.5 μM. Moreover, the ability of a variety of angiotensin peptides to inhibit 125/127 I-Ang 1-7 binding at 100 μM, Ang 1-7 was less potent that the other angiotensin peptides: Ang III > Ang II > Ang I ~ Ang IV > Ang 2-7 > Ang 1-7 ~ Ang 3-7. These studies suggest that the binding site for 125/127 I-Ang 1-7 is not specific for the putative Ang 1-7 receptor mas, and may represent a low affinity binding to the AT 1 or AT 2 receptor

scholarly journals Interaction of unsaturated fatty acids with anti-oestrogen-binding sites

1987 ◽  
Vol 243 (2) ◽  
pp. 359-364 ◽  
Author(s):  
P L H Hwang
Keyword(s):  
Fatty Acids ◽  
Oleic Acid ◽  
Binding Site ◽  
Binding Affinity ◽  
Binding Sites ◽  
Unsaturated Fatty Acids ◽  
Biological Significance ◽  
Competitive Inhibitor ◽  
Apparent Dissociation Constant ◽  
Endogenous Ligands

Specific high-affinity binding sites for non-steroidal anti-oestrogens such as tamoxifen have been identified in many animal and human tissues. The function of these binding sites and the nature of their endogenous ligands are currently unknown. Our laboratory has previously reported that unsaturated fatty acids at micromolar concentrations inhibited [3H]tamoxifen binding to the anti-oestrogen-binding sites in rat liver, raising the possibility that fatty acids might represent endogenous ligands for these sites. These studies have now been extended to examine the mechanism by which fatty acids inhibit [3H]tamoxifen binding to the anti-oestrogen-binding site. Saturation analysis revealed that increasing concentrations of oleic acid progressively decreased the apparent binding affinity of these sites for [3H]tamoxifen without decreasing the total number of binding sites; however, the apparent dissociation constant did not vary linearly with the prevailing oleic acid concentration, suggesting that the inhibition of [3H]tamoxifen binding by fatty acid was not competitive in nature. Kinetic studies of [3H]tamoxifen binding showed that oleic acid did not affect the rate of association, but increased the rate of dissociation of [3H]tamoxifen from the anti-oestrogen-binding site; the latter finding would not be expected if oleic acid acted as a competitive inhibitor. Furthermore, incubation of a rat microsomal fraction with [3H]oleic acid in the absence and presence of excess non-radioactively labelled tamoxifen also failed to demonstrate direct competition between oleic acid and tamoxifen for the same binding site. It is concluded that oleic acid, and presumably other unsaturated fatty acids, do not compete for the anti-oestrogen-binding site and probably reduce its tamoxifen-binding affinity by some other mechanism, such as perturbation of the lipid environment of the binding site. The biological significance of this interaction of unsaturated fatty acids with the anti-oestrogen-binding site remains to be elucidated.

scholarly journals Effective Use of Empirical Data for Virtual Screening against APJR GPCR Receptor

Molecules ◽  
2021 ◽  
Vol 26 (16) ◽  
pp. 4894
Author(s):  
Laura C. E. Manoliu ◽  
Eliza C. Martin ◽  
Adina L. Milac ◽  
Laurentiu Spiridon
Keyword(s):  
Virtual Screening ◽  
Binding Site ◽  
Large Scale ◽  
Neurodegenerative Disorder ◽  
Docking Simulation ◽  
Search Space ◽  
Design Strategies ◽  
Receptor Binding Site ◽  
In Silico Studies ◽  
The Central Nervous System

Alzheimer’s disease is a neurodegenerative disorder incompatible with normal daily activity, affecting one in nine people. One of its potential targets is the apelin receptor (APJR), a G-protein coupled receptor, which presents considerably high expression levels in the central nervous system. In silico studies of APJR drug-like molecule binding are in small numbers while high throughput screenings (HTS) are already sufficiently many to devise efficient drug design strategies. This presents itself as an opportunity to optimize different steps in future large scale virtual screening endeavours. Here, we ran a first stage docking simulation against a library of 95 known binders and 3829 generated decoys in an effort to improve the rescoring stage. We then analyzed receptor binding site structure and ligands binding poses to describe their interactions. As a result, we devised a simple and straightforward virtual screening Stage II filtering score based on search space extension followed by a geometric estimation of the ligand—binding site fitness. Having this score, we used an ensemble of receptors generated by Hamiltonian Monte Carlo simulation and reported the results. The improvements shown herein prove that our ensemble docking protocol is suited for APJR and can be easily extrapolated to other GPCRs.

Fluorometric study on conformational changes in the catalytic cycle of sarcoplasmic reticulum Ca2+-ATPase

1995 ◽  
Vol 15 (5) ◽  
pp. 317-326 ◽  
Author(s):  
Tohru Kanazawa ◽  
Hiroshi Suzuki ◽  
Takashi Daiho ◽  
Kazuo Yamasaki
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Binding Site ◽  
Conformational Changes ◽  
Binding Sites ◽  
Transmembrane Domain ◽  
Tryptophan Fluorescence ◽  
Cytoplasmic Domain ◽  
Catalytic Cycle ◽  
Atp Binding ◽  
Atp Binding Site

Changes in the fluoresence of N-acetyl-N′-(5-sulfo-1-naphthyl)ethylenediamine (EDANS), being attached to Cys-674 of sarcoplasmic reticulum Ca2+-ATPase without affecting the catalytic activity, as well as changes in the intrinsic tryptophan fluorescence were followed throughout the catalytic cycle by the steady-state measurements and the stopped-flow spectrofluorometry. EDANS-fluorescence changes reflect conformational changes near the ATP binding site in the cytoplasmic domain, while tryptophan-fluorescence changes most probably reflect conformational changes in or near the transmembrane domain in which the Ca2+ binding sites are located. Formation of the phosphoenzyme intermediates (EP) was also followed by the continuous flow-rapid quenching method. The kinetic analysis of EDANS-fluorescence changes and EP formation revealed that, when ATP is added to the calcium-activated enzyme, conformational changes in the ATP binding site occur in three successive reaction steps; conformational change in the calcium enzyme substrate complex, formation of ADP-sensitive EP, and transition of ADP-sensitive EP to ADP-insensitive EP. In contrast, the ATP-induced tryptophan-fluorescence changes occur only in the latter two steps. Thus, we conclude that conformational changes in the ATP binding site in the cytoplasmic domain are transmitted to the Ca2+-binding sites in the transmembrane domain in these latter two steps.

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