Incorporating replacement free energy of binding-site waters in molecular docking

2014 ◽  
Vol 82 (9) ◽  
pp. 1765-1776 ◽  
Author(s):  
Hanzi Sun ◽  
Lifeng Zhao ◽  
Shiming Peng ◽  
Niu Huang
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Binding Site ◽  
Free Energy Of Binding

Synthesis and Biological Evaluation of 3,4-Dihydro-2H-benzo[b][1,4]-oxazine-2-carboxylic Acid Derivatives as Antitubercular Agents

2020 ◽  
Vol 5 (2) ◽  
pp. 138-148
Author(s):  
Macchindra S. Tambe ◽  
Sonali Gadhe ◽  
Amit Choudhari ◽  
Dhiman Sarkar ◽  
Jaiprakash N. Sangshetti ◽  
...  
Keyword(s):  
Free Energy ◽  
Carboxylic Acid ◽  
Binding Site ◽  
Antitubercular Activity ◽  
Biological Evaluation ◽  
Binding Modes ◽  
Bacterial Strains ◽  
Antibacterial Screening ◽  
Free Energy Of Binding

A series of side chain modified structurally diverse 3,4-dihydro-2H-benzo[b][1,4]-oxazine-2-carboxylic acid derivatives were synthesized and characterized by IR, 1H NMR, 13C NMR and mass spectral study. All the newly synthesized compounds were examined for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Ra. The synthesized compounds exhibited minimum inhibitory concentration (IC50) ranging from 5.98 to >30 (μg/mL) against MtbH37Ra. Among the screened compounds, compounds 5a, 5c, 5d, 5f, 5g, 5h, 5I, 5j exhibited IC50 as 10.42, 11.81, 18.79, 5.98, 19.21, 24.81 and 14.81 μg/mL, respectively. The antibacterial screening study of these compounds was conducted against four different bacteria to asses there selectivity towards MTB. The antibacterial screening of all the synthesized compounds was conducted against four bacterial strains (Gram-negative strains: E.coli and S.aureus; Gram-positive strains: P. aeruginosa and B.subtilis. The compounds 5a, 5b, 5c, 5e and 5j showed higher antibacterial activity up to 7-25 μg/mL. Furthermore, molecular docking studies revealed the binding modes of the compounds in the binding site of the good agreement with the in vitro antitubercular screening. The compounds 5a, 5c and 5f with free energy of binding lower than -9.0 Kcal/mol binds more favourably at the binding site of panC as compared to other compounds. Specifically, the compound 5f with free energy of binding -9.6 Kcal/mol is indeed found more active in docking study as well as in the in vitro antitubercular screening. These findings open the possibility for potential lead for antituberculosis chemotherapy.

scholarly journals Intriguing Role of Water in Plant Hormone Perception

2021 ◽  
Author(s):  
Chuankai Zhao ◽  
Diego Eduardo Kleiman ◽  
Diwakar Shukla
Keyword(s):  
Free Energy ◽  
Plant Growth ◽  
Binding Site ◽  
Plant Hormones ◽  
Plant Hormone ◽  
Water Molecules ◽  
Water Displacement ◽  
Dynamics Simulations ◽  
Free Energy Of Binding

Plant hormones are small molecules that regulate plant growth, development, and responses to biotic and abiotic stresses. Plant hormones are specifically recognized by the binding site of their receptors. In this work, we investigated the role of water displacement and reorganization at the binding site of plant receptors on the binding of eight classes of phytohormones (auxin, jasmonate, gibberellin, strigolactone, brassinosteroid, cytokinin, salicylic acid, and abscisic acid) using extensive molecular dynamics simulations and inhomogeneous solvation theory. Our findings demonstrated that displacement of water molecules by phytohormones contributes to free energy of binding via entropy gain and is associated with free energy barriers. Also, our results have shown that displacement of unfavorable water molecules in the binding site can be exploited in rational agrochemical design. Overall, this study uncov- ers the role of water molecules in plant hormone perception, which creates new avenues for agrochemical design to target plant growth and development.

scholarly journals Molecular Docking, ADME Analysis, and Estimation of MM/GBSA Binding-Free Energies of Coumarin Derivatives as Potential Inhibitors of SARS CoV-2 Receptors

2020 ◽  
Author(s):  
Akhilesh Kumar Maurya ◽  
Nidhi Mishra
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Severe Acute Respiratory Syndrome ◽  
Specific Drug ◽  
Coumarin Derivatives ◽  
Free Energies ◽  
Potential Inhibitors ◽  
Stimulatory Factor ◽  
Free Energy Of Binding ◽  
Binding Free Energies

Abstract Coronavirus Disease (COVID-19) is recently declared pandemic (WHO) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Currently, there is no specific drug for the therapy of COVID-19. In the present study, in silico study have been done to find out possible inhibitors of SARS CoV-2. Coumarin derivatives with 2755 compounds were virtually screen against methyltransferase-stimulatory factor complex of NSP16 and NSP10, NSP15 Endoribonuclease, ADP ribose phosphatase (ADRP)of NSP3 and protease enzymes of SARS CoV-2. Docked top five compounds showed good docking scores and free energy of binding with the respective receptors. ADME/T analysis of docked compound shows the docked ligands are showing drug-likeness properties.

scholarly journals Identification of DNA gyrase Subunit a Mutations Associated with Ciprofloxacin Resistance in Staphylococcus aureus Isolated from Nasal Infection in Kurdistan-Iran

2017 ◽  
Vol 7 (1) ◽  
pp. 186
Author(s):  
Roya Darbani ◽  
Chiako Farshadfar ◽  
Somayeh Tavana ◽  
Hamidreza Saljoughi ◽  
Sheida Sadat Zonouri
Keyword(s):  
Staphylococcus Aureus ◽  
Free Energy ◽  
Molecular Docking ◽  
Dna Gyrase ◽  
Amino Acid Sequences ◽  
Nucleotide Sequencing ◽  
Molegro Virtual Docker ◽  
Fluoroquinolone Antibiotics ◽  
Ciprofloxacin Resistance ◽  
Free Energy Of Binding

Fluoroquinolone antibiotics such as ciprofloxacin are useful drugs against infections caused by Staphylococcus aureus and mutations in DNA gyrase which control bacterial DNA topology, can be one of the reason of occurrence resistance to this class of antibiotics. Therefore finding new mutations and study of the quinolone interaction with mutated GyrA can provide important issues for explanation resistance. In this study 5 ciprofloxacin resistance Staphylococcus aureus isolated among 50 collected S.aureus strains. By PCR testing, gyrA genes in resistance strains was amplified and nucleotide sequencing was done. Nucleotide sequences translate to amino acid sequences then by blastp homology between each GyrA mutant and reference GyrA were compared and mutations were recognized, at last molecular docking were done for GyrA protein and ciprofloxacin, based on free energy of binding decide if the mutations are responsible of resistance or not. The results show glutamic acid and threonine adjacent to each other in common positions 21-22, 32-33, 65-66, 84-85, 101-102, 106-107, 128-129 and 138-139 in all 5 strains were inserted . In order to finding association between mutations and ciprofloxacin resistance molecular docking by Molegro Virtual Docker 5.5 was done. Free energy of binding between reference GyrA- ciprofloxacin and mutant GyrA- ciprofloxacin were -92.3477 and -73.1642 respectively. We conclude different mutations can be affected structure of GyrA and make ciprofloxacin resistance. Finding these kinds of mutations are important and preventing them is indispensable.

Binding Affinity of a Small Molecule to an Amorphous Polymer in a Solvent. Part 1: Free Energy of Binding to a Binding Site

Langmuir ◽  
2011 ◽  
Vol 27 (20) ◽  
pp. 12381-12395 ◽  
Author(s):  
Surasak Chunsrivirot ◽  
Ying Diao ◽  
Bernhardt L. Trout
Keyword(s):  
Free Energy ◽  
Binding Site ◽  
Binding Affinity ◽  
Small Molecule ◽  
Amorphous Polymer ◽  
Free Energy Of Binding

scholarly journals Molecular docking approach to elucidate metabolic detoxification pathway of polycyclic aromatic hydrocarbons

2021 ◽  
pp. 150-161
Author(s):  
Mohammad Kalim Ahmad Khan ◽  
Salman Akhtar ◽  
Fahad Al-Khodairy
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Aromatic Hydrocarbons ◽  
Glutathione S Transferase ◽  
Drug Discovery And Development ◽  
Docking Approach ◽  
Polycyclic Aromatic ◽  
Metabolic Detoxification ◽  
Free Energy Of Binding ◽  
Detoxification Pathway

This study assessed the molecular interactions of (±)-anti-and-syn- dibenzo[a,l]pyrene-11,12-diol-13,14-epoxide (DBPDE), 7,12- dimethylbenz[a]anthracene-3,4-diol-1,2-epoxide (DMBADE), N2- hydroxylated-PhIP(N2-OH-PhIP), (±)-anti-and-syn-benzo[a]pyrene-7,8-diol- 9,10-epoxide (BPDE) with various Glutathione S-transferase (GST) and N- acetyltransferase (NAT) isozymes. Our in-silico data revealed that GSTP1 (- 8.83 kcal/mol), showing more plausible binding as compared to GSTM1 (-8.74 kcal/mol) and GSTA1 (ΔG: -8.03 kcal/mol) against (-)-anti-DBPDE and (+)- syn-DBPDE. We also investigated the involvement of GST and NAT isozymes in the conjugation of DMBADE andN2-OH-PhIP as a control despite their preferred routes sulfonation and glucuronidation for detoxification. The findings exhibited feeble binding of different classes of GSTs with metabolites of DMBA and PhIP, as highlighted by their free energy of binding. The enzymatic activity of GSTM1 against the most potent diol-epoxide of benzo[a]pyrene (BP), (+)-anti-BPDE, and (+)-syn-BPDE followed by GSTP1 and GSTA1 has well documented. In addition, these findings provide new perspectives for most probable mechanistic details of the detoxification pathway of PAHs and xenobiotics useful in combination therapy for future ligand-based drug discovery and development.

scholarly journals ANTIBACTERIAL ACTIVITY OF AKAR KUNING (ARCANGELISIA FLAVA) SECONDARY METABOLITES: MOLECULAR DOCKING APPROACH

2018 ◽  
Vol 11 (11) ◽  
pp. 447 ◽  
Author(s):  
Mohammad Rizki Fadhil Pratama ◽  
Suratno S ◽  
Evi Mulyani
Keyword(s):  
Cell Wall ◽  
Free Energy ◽  
Molecular Docking ◽  
Secondary Metabolites ◽  
Acid Synthesis ◽  
Allosteric Site ◽  
Protein Nucleic Acid ◽  
Cell Wall Inhibition ◽  
Inhibitor Of Protein Synthesis ◽  
Free Energy Of Binding

Objectives: Akar kuning (Arcangelisia flava) was known to have various pharmacological activities including as antibacterial. Several Gram-positive and Gram-negative bacteria show response to akar kuning secondary metabolites, although the type of metabolites that inhibit the growth of each type of bacteria not yet known. This study aims to obtain the prediction of metabolites from akar kuning with the greatest antibacterial potential against various types of antibacterial receptors.Methods: Molecular docking was performed using Autodock Vina 1.1.2 on several secondary metabolites of akar kuning against active site of several antibacterial receptors that were known for many antibiotics including as cell wall, protein, nucleic acid synthesis inhibitors, and antimetabolites. The main parameter used was the free energy of binding as affinity marker.Results: The docking results show that among 11 metabolites studied, 6-hydroxyfibraurin, berberine, and fibleucin provided the lowest free energy of binding between 11 antibacterial receptors compared with natural substrates or inhibitors from each receptor. Interesting results show by berberine as inhibitor of protein synthesis with possibility of allosteric site discovery. Berberine also shows more than 75% similarity with natural substrate of cell wall inhibition receptor, indicating possible similar type of interaction.Conclusion: Overall, it seems that for the selected secondary metabolites of akar kuning, the main mechanism of action was the inhibition of protein and cell wall synthesis, which was shown by berberine.

PLAUSIBLE BINDING MODE OF THE ACTIVE α4β1 ANTAGONIST, MK-0617, DETERMINED BY DOCKING AND FREE ENERGY CALCULATIONS

2013 ◽  
Vol 12 (02) ◽  
pp. 1250108 ◽  
Author(s):  
C. MANUEL CARLEVARO ◽  
JOÃO HERMÍNIO MARTINS-DA-SILVA ◽  
WILSON SAVINO ◽  
ERNESTO RAÚL CAFFARENA
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Binding Site ◽  
Binding Mode ◽  
Free Energy Calculations ◽  
Receptor Interaction ◽  
Cell Trafficking ◽  
Integrin Binding Site ◽  
Energy Perturbation ◽  
Dynamics Simulations

In the last years, the development of small molecule antagonists of VLA-4 for the treatment of diseases, where cell trafficking and activation are important, has increased considerably. Among them, the MK-0617 ligand has proven to be a highly potent and orally active α4β1 antagonist. However, the binding mode of this ligand in the integrin binding site remains unknown. Herein we report a thermodynamic analysis of the interaction between MK-0617 (and one of its isomers) and the VLA-4 protein using molecular docking and the free energy perturbation calculations, based on a comparative model of the α4β1 receptor. Initial complex coordinates were taken from molecular docking assays and submitted to alchemical transformations. Free energy of binding ΔΔG values, derived from experimental IC50 values, were taken as a parameter for determining the most likely binding mode. In addition, molecular dynamics simulations of these ligands within the α4β1 binding site were carried out to elucidate the binding energy profile and identify the most significant residues. Our results indicate that MK-0617 fits within the binding site in a stretched conformation, pointing the carboxylate group towards the MIDAS ion. We observe that, despite the fact that the main contribution to the energetic binding process is due to the electrostatic ion contribution, the nonpolar contribution is not negligible. Additionally, a network of hydrogen bonds participate in stabilizing the ligand-receptor interaction.

Antibody–oligosaccharide interactions: the synthesis of 2-deoxy-α-L-rhamnose containing oligosaccharide haptens related to Shigella flexneri variant Y antigen

1993 ◽  
Vol 71 (1) ◽  
pp. 125-134 ◽  
Author(s):  
H. Rizk Hanna ◽  
David R. Bundle
Keyword(s):  
Amino Acids ◽  
Monoclonal Antibody ◽  
Free Energy ◽  
Binding Site ◽  
Shigella Flexneri ◽  
Relative Increase ◽  
Protecting Groups ◽  
The Subject ◽  
Inhibitory Power ◽  
Free Energy Of Binding

A series of di- and trisaccharide glycosides based on the α-L-Rha(1 → 3)β-D-GlcNAc and α-L-Rha(1 → 3)α-L-Rha(1 → 3)β-D-GlcNAc elements have been synthesized to locate the minimal oligosaccharide determinant of the Shigella flexneri O-polysaccharide, which is built from a tetrasaccharide repeating unit, [ → 2) α-L-Rhap(1 → 2)α-L-Rhap(1 → 3)α-L-Rhap(1 → 3)β-D-GlcNAcp(1-]n. These compounds also serve to identify the carbohydrate surface of the Shigella antigen that interacts with a monoclonal antibody, currently the subject of crystallographic studies. Two strategies utilizing suitably protected glycals 1 and 19 were employed to obtain analogs bearing either terminal or glycosylated 2,6-dideoxy-α-L-arabino-hexopyranosyl (2-deoxy-α-L-rhamnopyranosyl) residues. N-Iodosuccinimide activation of the glycals in the presence of selectively protected mono- and disaccharide alcohols afforded 2-deoxy-2-iodo-α-L-rhamnopyranosides and these were ultimately reduced during deprotection stages to afford the desired functionality. Di-O-acetyl L-rhamnal 1 reacted with monosaccharides 2 and 7, and with disaccharide 11, to yield disaccharides 4 and 8, and trisaccharide 12, each bearing a terminal 2-deoxy-α-L-rhamnopyranosyl residue. The selectively protected 3-O-benzoyl-4-O-benzyl-L-rhamnal 19 was synthesized from L-rhamnal and used to prepared trisaccharide 22, which contained an internal 2-deoxy-2-iodo-α-L-rhamnopyranosyl unit. Removal of protecting groups gave the oligosaccharides 6, 10, 14, and 23. Oligosaccharides that contained a 2-deoxy-α-L-rhamnopyranosyl residue showed enhanced inhibitory power: in the case of trisaccharide 23 a 1.8 kcal mol−1 relative increase in free energy of binding compared to a larger pentasaccharide epitope, α-L-Rhap(1 → 2)α-L-Rhap(1 → 3)α-L-Rhap(1 → 3)β-D-GlcNAcp(1 → 2)α-L-Rhap-1 → OMe. These data suggest that the rhamnose O–2 hydroxyl of residue C points toward and has important interactions with binding site amino acids.

MOLECULAR DOCKING ANALYSES OF SOME CYCLOHEXADIENE DERIVATIVES

2021 ◽  
Author(s):  
Jelena Đorović Jovanović ◽  
◽  
Dušan Dimić ◽  
Marijana Stanojević Pirković ◽  
Svetlana Jeremić ◽  
...  
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Docking Study ◽  
Molecular Docking Study ◽  
Inhibitory Potency ◽  
Docking Simulations ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Autodock 4.0 ◽  
Free Energy Of Binding

The molecular docking study was performed with aim to examine the inhibitory potency of two selected cyclohexadiene derivatives (cis-(1S)-3-Fluoro-3,5-cyclohexadiene-1,2-diol (1), and 1,1′-(3,5-Cyclohexadiene-1,3-diyl)dibenzene (2)). The inhibitory potency of compounds 1 and 2 was investigated toward Urokinase Type Plasminogen Activator (uPa). For this purpose AutoDock 4.0 software was used. The thermodynamic parameters achieved from molecular docking simulations, free energy of binding (ΔGbind) and inhibition constant (Ki), are analyzed and discussed. The compound 2 shows better inhibitory potency through uPa, than compound 1.

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