QM/MM calculations and MD simulations of acetolactate decarboxylase to reveal substrate R/S-acetolactate binding mode and stereoselective catalytic mechansim

Simulations of molecular dynamics (MD) are playing an increasingly important role in structure-based drug discovery (SBDD). Here we review the use of MD for proteins in aqueous solvation, organic/aqueous mixed solvents (MDmix) and with small ligands, to the classic SBDD problems: Binding mode and binding free energy predictions. The simulation of proteins in their condensed state reveals solvent structures and preferential interaction sites (hot spots) on the protein surface. The information provided by water and its cosolvents can be used very effectively to understand protein ligand recognition and to improve the predictive capability of well-established methods such as molecular docking. The application of MD simulations to the study of the association of proteins with drug-like compounds is currently only possible for specific cases, as it remains computationally very expensive and labor intensive. MDmix simulations on the other hand, can be used systematically to address some of the common tasks in SBDD. With the advent of new tools and faster computers we expect to see an increase in the application of mixed solvent MD simulations to a plethora of protein targets to identify new drug candidates.

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Unraveling Sugar Binding Modes to DC-SIGN by Employing Fluorinated Carbohydrates

Molecules ◽

10.3390/molecules24122337 ◽

2019 ◽

Vol 24 (12) ◽

pp. 2337 ◽

Cited By ~ 15

Author(s):

J. Daniel Martínez ◽

Pablo Valverde ◽

Sandra Delgado ◽

Cecilia Romanò ◽

Bruno Linclau ◽

...

Keyword(s):

Protein Interactions ◽

Viral Infections ◽

Md Simulations ◽

Binding Mode ◽

Intercellular Adhesion Molecule ◽

Binding Modes ◽

Binding Epitope ◽

First Time ◽

Biomedical Interest ◽

Specific Sugar

A fluorine nuclear magnetic resonance (19F-NMR)-based method is employed to assess the binding preferences and interaction details of a library of synthetic fluorinated monosaccharides towards dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN), a lectin of biomedical interest, which is involved in different viral infections, including HIV and Ebola, and is able to recognize a variety of self- and non-self-glycans. The strategy employed allows not only screening of a mixture of compounds, but also obtaining valuable information on the specific sugar–protein interactions. The analysis of the data demonstrates that monosaccharides Fuc, Man, Glc, and Gal are able to bind DC-SIGN, although with decreasing affinity. Moreover, a new binding mode between Man moieties and DC-SIGN, which might have biological implications, is also detected for the first time. The combination of the 19F with standard proton saturation transfer difference (1H-STD-NMR) data, assisted by molecular dynamics (MD) simulations, permits us to successfully define this new binding epitope, where Man coordinates a Ca2+ ion of the lectin carbohydrate recognition domain (CRD) through the axial OH-2 and equatorial OH-3 groups, thus mimicking the Fuc/DC-SIGN binding architecture.

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A boosted unbiased molecular dynamics method for predicting ligands binding mechanisms: probing the binding pathway of dasatinib to Src-kinase

Bioinformatics ◽

10.1093/bioinformatics/btaa565 ◽

2020 ◽

Vol 36 (18) ◽

pp. 4714-4720

Author(s):

Farzin Sohraby ◽

Mostafa Javaheri Moghadam ◽

Masoud Aliyar ◽

Hassan Aryapour

Keyword(s):

Molecular Dynamics ◽

Ligand Binding ◽

Md Simulation ◽

Src Kinase ◽

Deep Understanding ◽

Md Simulations ◽

Binding Mode ◽

Supplementary Information ◽

Computational Resources ◽

Binding Mechanisms

Abstract Summary Small molecules such as metabolites and drugs play essential roles in biological processes and pharmaceutical industry. Knowing their interactions with biomacromolecular targets demands a deep understanding of binding mechanisms. Dozens of papers have suggested that discovering of the binding event by means of conventional unbiased molecular dynamics (MD) simulation urges considerable amount of computational resources, therefore, only one who holds a cluster or a supercomputer can afford such extensive simulations. Thus, many researchers who do not own such resources are reluctant to take the benefits of running unbiased MD simulation, in full atomistic details, when studying a ligand binding pathway. Many researchers are impelled to be content with biased MD simulations which seek its validation due to its intrinsic preconceived framework. In this work, we have presented a workable stratagem to encourage everyone to perform unbiased (unguided) MD simulations, in this case a protein–ligand binding process, by typical desktop computers and so achieve valuable results in nanosecond time scale. Here, we have described a dynamical binding’s process of an anticancer drug, the dasatinib, to the c-Src kinase in full atomistic details for the first time, without applying any biasing force or potential which may lead the drug to artificial interactions with the protein. We have attained multiple independent binding events which occurred in the nanosecond time scales, surprisingly as little as ∼30 ns. Both the protonated and deprotonated forms of the dasatinib reached the crystallographic binding mode without having any major intermediate state during induction. Availability and implementation The links of the tutorial and technical documents are accessible in the article. Supplementary information Supplementary data are available at Bioinformatics online.

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Discovery of novel sphingosine kinase 1 inhibitorsvia structure-based hierarchical virtual screening

MedChemComm ◽

10.1039/c4md00312h ◽

2015 ◽

Vol 6 (3) ◽

pp. 413-417 ◽

Cited By ~ 5

Author(s):

Xiaojian Wang ◽

Chenbin Sun ◽

Liang Fang ◽

Dali Yin

Keyword(s):

Virtual Screening ◽

Sphingosine Kinase ◽

Md Simulations ◽

Binding Pocket ◽

Binding Mode ◽

Positive Control ◽

Biological Evaluation ◽

U937 Cells ◽

Sphingosine Kinase 1 ◽

Inhibitory Activities

Hierarchical structure-based virtual screening against the sphingosine kinase 1(SphK1) binding pocket was performed. 25 compounds were selected for biological evaluation. Compound 25 exhibited comparable SphK1 and SphK2 inhibitory activities and anti-proliferative effects on U937 cells to the positive control N,N-dimethylsphingosine (DMS) 1. Further molecule dynamic (MD) simulations revealed the binding mode between SphK1 and 25.

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A combination of solid-state NMR and MD simulations reveals the binding mode of a rhomboid protease inhibitor

Chemical Science ◽

10.1039/d1sc02146j ◽

2021 ◽

Author(s):

Claudia Bohg ◽

Carl Öster ◽

Tillmann Utesch ◽

Susanne Bischoff ◽

Sascha Lange ◽

...

Keyword(s):

Solid State ◽

Protease Inhibitor ◽

Solid State Nmr ◽

Md Simulations ◽

Binding Mode ◽

Selective Inhibitors ◽

Intramembrane Proteolysis ◽

Rhomboid Protease ◽

Intramembrane Proteases ◽

Pharmacological Targets

Intramembrane proteolysis plays a fundamental role in many biological and pathological processes. Intramembrane proteases thus represent promising pharmacological targets, but few selective inhibitors have been identified. This is in contrast...

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Fragment Pose Prediction Using Non-Equilibrium Candidate Monte Carlo and Molecular Dynamics Simulations

10.26434/chemrxiv.10032218 ◽

2019 ◽

Author(s):

Nathan M. Lim ◽

Meghan Osato ◽

Gregory L. Warren ◽

David L. Mobley

Keyword(s):

Crystal Structure ◽

Molecular Dynamics ◽

Monte Carlo ◽

Ligand Binding ◽

Md Simulations ◽

Binding Mode ◽

Protein Crystal ◽

Pose Prediction ◽

Binding Modes ◽

Non Equilibrium

<div>Part of early stage drug discovery involves determining how molecules may bind to the target protein. Through understanding where and how molecules bind, chemists can begin to build ideas on how to design improvements to increase binding affinities. In this retrospective study, we compare how computational approaches like docking, molecular dynamics (MD) simulations, and a non-equilibrium candidate Monte Carlo (NCMC) based method (NCMC+MD) perform in predicting binding modes for a set of 12 fragment-like molecules which bind to soluble epoxide hydrolase. We evaluate each method's effectiveness in identifying the dominant binding mode and finding any additional binding modes (if any). Then, we compare our predicted binding modes to experimentally obtained X-ray crystal structures.</div><div>We dock each of the 12 small molecules into the apo-protein crystal structure and then run simulations up to 1 microsecond each. Small and fragment-like molecules likely have smaller energy barriers separating different binding modes by virtue of relatively fewer and weaker interactions relative to drug-like molecules, and thus likely undergo more rapid binding mode transitions. We expect, thus, to see more rapid transitions betweeen binding modes in our study. </div><div><br></div><div>Following this, we build Markov State Models (MSM) to define our stable ligand binding modes. We investigate if adequate sampling of ligand binding modes and transitions between them can occur at the microsecond timescale using traditional MD or a hybrid NCMC+MD simulation approach. Our findings suggest that even with small fragment-like molecules, we fail to sample all the crystallographic binding modes using microsecond MD simulations, but using NCMC+MD we have better success in sampling the crystal structure while obtaining the correct populations.</div>

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Targeting Peptidyl-prolyl Cis-trans Isomerase NIMA-interacting 1: A Structure-based Virtual Screening Approach to Find Novel Inhibitors

Current Computer - Aided Drug Design ◽

10.2174/1573409915666191025114009 ◽

2020 ◽

Vol 16 (5) ◽

pp. 605-617 ◽

Cited By ~ 1

Author(s):

Kauê Santana da Costa ◽

João M. Galúcio ◽

Deivid Almeida de Jesus ◽

Guelber Cardoso Gomes ◽

Anderson Henrique Lima e Lima ◽

...

Keyword(s):

Inhibitory Activity ◽

Binding Free Energy ◽

Md Simulations ◽

Binding Mode ◽

Free Energy Calculations ◽

Pentacyclic Triterpenoids ◽

Substrate Peptide ◽

Molecular Mechanism Of Action ◽

Structural Insights ◽

Virtual Screening Approach

Background : Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) is an enzyme that isomerizes phosphorylated serine or threonine motifs adjacent to proline residues. Pin1 has important roles in several cellular signaling pathways, consequently impacting the development of multiple types of cancers. Methods: Based on the previously reported inhibitory activity of pentacyclic triterpenoids isolated from the gum resin of Boswellia genus against Pin1, we designed a computational experiment using molecular docking, pharmacophore filtering, and structural clustering allied to molecular dynamics (MD) simulations and binding free energy calculations to explore the inhibitory activity of new triterpenoids against Pin1 structure. Results: Here, we report different computational evidence that triterpenoids from neem (Azadirachta indica A. Juss), such as 6-deacetylnimbinene, 6-Oacetylnimbandiol, and nimbolide, replicate the binding mode of the Pin1 substrate peptide, interacting with high affinity with the binding site and thus destabilizing the Pin1 structure. Conclusion: Our results are supported by experimental data, and provide interesting structural insights into their molecular mechanism of action, indicating that their structural scaffolds could be used as a start point to develop new inhibitors against Pin1.

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The Interaction of Fluorinated Glycomimetics with DC-SIGN: Multiple Binding Modes Disentangled by the Combination of NMR Methods and MD Simulations

Pharmaceuticals ◽

10.3390/ph13080179 ◽

2020 ◽

Vol 13 (8) ◽

pp. 179

Author(s):

J. Daniel Martínez ◽

Angela S. Infantino ◽

Pablo Valverde ◽

Tammo Diercks ◽

Sandra Delgado ◽

...

Keyword(s):

Md Simulations ◽

Binding Mode ◽

Matrix Analysis ◽

Binding Modes ◽

Receptor Complexes ◽

Multiple Binding ◽

Std Nmr ◽

Complex Glycans ◽

Complete Relaxation Matrix Analysis ◽

Nmr Methods

Fluorinated glycomimetics are frequently employed to study and eventually modulate protein–glycan interactions. However, complex glycans and their glycomimetics may display multiple binding epitopes that enormously complicate the access to a complete picture of the protein–ligand complexes. We herein present a new methodology based on the synergic combination of experimental 19F-based saturation transfer difference (STD) NMR data with computational protocols, applied to analyze the interaction between DC-SIGN, a key lectin involved in inflammation and infection events with the trifluorinated glycomimetic of the trimannoside core, ubiquitous in human glycoproteins. A novel 2D-STD-TOCSYreF NMR experiment was employed to obtain the experimental STD NMR intensities, while the Complete Relaxation Matrix Analysis (CORCEMA-ST) was used to predict that expected for an ensemble of geometries extracted from extensive MD simulations. Then, an in-house built computer program was devised to find the ensemble of structures that provide the best fit between the theoretical and the observed STD data. Remarkably, the experimental STD profiles obtained for the ligand/DC-SIGN complex could not be satisfactorily explained by a single binding mode, but rather with a combination of different modes coexisting in solution. Therefore, the method provides a precise view of those ligand–receptor complexes present in solution.

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Potential Anti-Alzheimer Agents from Guanidinyl Tryptophan Derivatives with Activities of Membrane Adhesion and Conformational Transition Inhibitions

Molecules ◽

10.3390/molecules26164863 ◽

2021 ◽

Vol 26 (16) ◽

pp. 4863

Author(s):

Pathomwat Wongrattanakamon ◽

Jutamas Jiaranaikulwanitch ◽

Opa Vajragupta ◽

Supat Jiranusornkul ◽

Chalermpong Saenjum ◽

...

Keyword(s):

Lipid Membrane ◽

Conformational Transition ◽

Md Simulations ◽

Bilayer Lipid Membrane ◽

Binding Mode ◽

Amino Acid Residues ◽

Membrane Adhesion ◽

Further Development ◽

Tryptophan Derivatives

Guanidinyl tryptophan derivatives TGN1, TGN2, TGN3, and TGN4 were synthesized, and these compounds were shown to possess in vitro inhibitory activity for amyloid aggregation in a previous study. Nevertheless, the influence of the TGN series of compounds on the binding and permeation behaviors of an Aβ monomer to the cell membranes was not elucidated. In this study, we investigated the effect of compounds in the TGN series on the behavior of an Aβ monomer regarding its toxicity toward the bilayer lipid membrane using molecular dynamics (MD) simulation. MD simulations suggest that TGN4 is a potential agent that can interfere with the movement of the Aβ monomer into the membrane. The MM-GBSA result demonstrated that TGN4 exhibits the highest affinity to the Aβ1–42 monomer but has the lowest affinity to the bilayer. Moreover, TGN4 also contributes to a decrease in the binding affinity between the Aβ1–42 monomer and the POPC membrane. Regarding the results of the binding mode and conformational analyses, a high number of amino-acid residues were shown to provide the binding interactions between TGN4 and the Aβ1–42 monomer. TGN4 also reduces the conformational transition of the Aβ1–42 monomer by means of interacting with the monomer. The present study presents molecular-level insights into how the TGN series of compounds affect the membrane adsorption and the conformational transition of the Aβ1–42 monomer, which could be valuable for the further development of new anti-Alzheimer agents.

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Enhancing Paraoxon Binding to Organophosphorus Hydrolase Active Site

10.26434/chemrxiv.13930874.v1 ◽

2021 ◽

Author(s):

Léa El Khoury ◽

David Mobley ◽

Dongmei Ye ◽

Susan Rempe

Keyword(s):

Active Site ◽

Binding Free Energy ◽

Hot Spot ◽

Circulatory System ◽

Kinetic Studies ◽

Md Simulations ◽

Binding Mode ◽

Hydrolytic Activity ◽

Free Energy Calculations ◽

Organophosphorus Hydrolase

<p>Organophosphorus (OP) compounds are among the most toxic of chemical substances and widely used as insecticides, pesticides, and chemical warfare agents. The most important enzyme inhibited by OP compounds is acetylcholinesterase (AChe). Inactivation of AChe function results in the accumulation of neurotransmitter, leading to death due to serious respiratory disorders. Organophosphorus hydrolase (OPH), also called phosphotriesterase, is a homo-dimeric metalloenzyme that can hydrolyze various OP agents in the circulatory system, resulting in products that are generally of reduced toxicity. The best OPH substrate found to date is the insecticide diethyl p-nitrophenyl phosphate (paraoxon). Most structural and kinetic studies assume that the binding orientation of paraoxon is identical to that of diethyl 4-methylbenzylphosphonate, which is the only substrate analog co-crystallized with OPH. In the current work, we used a combined docking and molecular dynamics (MD) approach to predict the likely binding mode of paraoxon in the OPH active site. We identified a potential binding mode of paraoxon that does not match the binding mode of diethyl 4-methylbenzylphosphonate. Then, we used the predicted binding mode to run MD simulations on the wild type (WT) OPH complexed with paraoxon, and OPH mutants complexed with paraoxon. Additionally, we identified 3 hot-spot residues (D253, H254, and I255) involved in the stability of the OPH active site. To further assess these predictions, we then experimentally assayed single and double mutants involving these residues (D253E, H254S, I255S, D253E-H254R and D253E-I255G) for hydrolytic activity against paraoxon. Computational structural analysis of protein-substrate dynamics shows different hydrogen bonding profiles for mutants involving D253 (D253E, D253E-H254R, and D253E-I255G) compared to WT OPH. Additionally, the binding free energy calculations and the experimental kinetics (particularly, <i>k</i><sub>cat</sub> and <i>K<sub>M</sub></i>) of the reactions between each OPH mutant and paraoxon show that mutated forms D253E, D253E-H254R, and D253E-I255G exhibit enhanced activity over WT OPH. Interestingly, our experimental results show that the activity of the double mutant D253E-H254R increased by 19-fold compared to WT OPH.</p>

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