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

Free Energy of Binding of a Small Molecule to an Amorphous Polymer in a Solvent

Langmuir ◽  
2011 ◽  
Vol 27 (11) ◽  
pp. 6910-6919 ◽  
Author(s):  
Surasak Chunsrivirot ◽  
Bernhardt L. Trout
Keyword(s):  
Free Energy ◽  
Small Molecule ◽  
Amorphous Polymer ◽  
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 Binding affinity and conformational preferences influence kinetic stability of short oligonucleotides on carbon nanotubes

2020 ◽  
Author(s):  
Ali Alizadehmojarad ◽  
Xingcheng Zhou ◽  
Abraham G Beyene ◽  
Kevin Chacon ◽  
Younghun Sung ◽  
...  
Keyword(s):  
Carbon Nanotubes ◽  
Free Energy ◽  
Binding Affinity ◽  
Md Simulations ◽  
Kinetic Stability ◽  
Ring Formation ◽  
Structural Motifs ◽  
Nucleotide Interactions ◽  
Free Energy Of Binding ◽  
The Relationship

DNA-wrapped single walled carbon nanotubes (SWNTs) have found a widespread use in a variety of nanotechnology applications. Yet, the relationship between structural conformation, binding affinity and kinetic stability of these polymers on SWNTs remains poorly understood. Here, we used molecular dynamics (MD) simulations and experiments to explore this relationship for short oligonucleotides adsorbed on SWNTs. First, using classical MD simulations of oligonucleotide-(9,4)-SWNT hybrid complexes, we explored the relationship between ssDNA and ssRNA surface conformation and sequence chemistry. We screened the conformation of 36 sequences of short ssDNA and ssRNA polymers on (9,4) SWNT, where the contour lengths were selected so the polymers can, to a first approximation, wrap once around the SWNT circumference. From these screens, we identified structural motifs that we broadly classified into rings and non-rings. Then, several sequences were selected for detailed investigations. We used temperature replica exchange MD calculations to compute two-dimensional free energy landscapes characterizing the conformations of select sequences. Ring conformations seemed to be driven primarily by sequence chemistry. Specifically, strong (n,n+2) nucleotide interactions and the ability of the polymer to form compact structures, as for example, through sharp bends in the nucleotide backbone, correlated with ring-forming propensity. However, ring-formation probability was found to be uncorrelated with free energy of oligonucleotide binding to SWNTs (∆Gbind). Conformational analyses of oligonucleotides, computed free energy of binding of oligonucleotides to SWNTs, and experimentally determined kinetic stability measurements show that ∆Gbind is the primary correlate for kinetic stability. The probability of the sequence to adopt a compact, ring-like conformation is shown to play a secondary role that still contributes measurably to kinetic stability. For example, sequences that form stable compact rings (C-rich sequences) could compensate for their relatively lower ∆Gbind and exhibit kinetic stability, while sequences with strong ∆Gbind (such as (TG)3(GT)3) were found to be kinetically stable despite their low ring formation propensity. We conclude that the stability of adsorbed oligonucleotides is primarily driven by its free energy of binding and that if ring-like structural motifs form, they would contribute positively to stability.

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.

Binding Affinity of a Small Molecule to an Amorphous Polymer in a Solvent. Part 2: Preferential Binding to Local Sites on a Surface

Langmuir ◽  
2011 ◽  
Vol 27 (20) ◽  
pp. 12396-12404 ◽  
Author(s):  
Surasak Chunsrivirot ◽  
Erik Santiso ◽  
Bernhardt L. Trout
Keyword(s):  
Binding Affinity ◽  
Small Molecule ◽  
Amorphous Polymer ◽  
Preferential Binding

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

scholarly journals Predicting Ligand Binding Affinity with Alchemical Free Energy Methods in a Polar Model Binding Site

2009 ◽  
Vol 394 (4) ◽  
pp. 747-763 ◽  
Author(s):  
Sarah E. Boyce ◽  
David L. Mobley ◽  
Gabriel J. Rocklin ◽  
Alan P. Graves ◽  
Ken A. Dill ◽  
...  
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
Binding Site ◽  
Binding Affinity ◽  
Energy Methods ◽  
Polar Model ◽  
Alchemical Free Energy

scholarly journals Overview of the SAMPL6 pKa Challenge: Evaluating small molecule microscopic and macroscopic pKa predictions

2020 ◽  
Author(s):  
Mehtap Işık ◽  
Ariën S. Rustenburg ◽  
Andrea Rizzi ◽  
M. R. Gunner ◽  
David L. Mobley ◽  
...  
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
Binding Affinity ◽  
Small Molecule ◽  
Kinase Inhibitors ◽  
Dissociation Constants ◽  
Binding Free Energy ◽  
Acid Dissociation ◽  
Prediction Methods ◽  
Protonation State

AbstractThe prediction of acid dissociation constants (pKa) is a prerequisite for predicting many other properties of a small molecule, such as its protein-ligand binding affinity, distribution coefficient (log D), membrane permeability, and solubility. The prediction of each of these properties requires knowledge of the relevant protonation states and solution free energy penalties of each state. The SAMPL6 pKa Challenge was the first time that a separate challenge was conducted for evaluating pKa predictions as part of the Statistical Assessment of Modeling of Proteins and Ligands (SAMPL) exercises. This challenge was motivated by significant inaccuracies observed in prior physical property prediction challenges, such as the SAMPL5 log D Challenge, caused by protonation state and pKa prediction issues. The goal of the pKa challenge was to assess the performance of contemporary pKa prediction methods for drug-like molecules. The challenge set was composed of 24 small molecules that resembled fragments of kinase inhibitors, a number of which were multiprotic. Eleven research groups contributed blind predictions for a total of 37 pKa distinct prediction methods. In addition to blinded submissions, four widely used pKa prediction methods were included in the analysis as reference methods. Collecting both microscopic and macroscopic pKa predictions allowed in-depth evaluation of pKa prediction performance. This article highlights deficiencies of typical pKa prediction evaluation approaches when the distinction between microscopic and macroscopic pKas is ignored; in particular, we suggest more stringent evaluation criteria for microscopic and macroscopic pKa predictions guided by the available experimental data. Top-performing submissions for macroscopic pKa predictions achieved RMSE of 0.7-1.0 pKa units and included both quantum chemical and empirical approaches, where the total number of extra or missing macroscopic pKas predicted by these submissions were fewer than 8 for 24 molecules. A large number of submissions had RMSE spanning 1-3 pKa units. Molecules with sulfur-containing heterocycles or iodo and bromo groups were less accurately predicted on average considering all methods evaluated. For a subset of molecules, we utilized experimentally-determined microstates based on NMR to evaluate the dominant tautomer predictions for each macroscopic state. Prediction of dominant tautomers was a major source of error for microscopic pKa predictions, especially errors in charged tautomers. The degree of inaccuracy in pKa predictions observed in this challenge is detrimental to the protein-ligand binding affinity predictions due to errors in dominant protonation state predictions and the calculation of free energy corrections for multiple protonation states. Underestimation of ligand pKa by 1 unit can lead to errors in binding free energy errors up to 1.2 kcal/mol. The SAMPL6 pKa Challenge demonstrated the need for improving pKa prediction methods for drug-like molecules, especially for challenging moieties and multiprotic molecules.

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.

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