Investigation of Pharmaceutical Importance of 2H-Pyran-2-One Analogues via Computational Approaches

Highly functionalized spirocyclic ketals were synthesized through asymmetric oxidative spirocyclization via carbanion-induced ring transformation of 2H-pyran-2-ones with 1,4-cyclohexandione monoethyleneketal under alkaline conditions. Further acidic-hydrolysis of obtained spirocyclic ketals yields highly substituted 2-tetralone in good yield. Computational analysis based on the DFT calculations and MD simulations has been performed in order to predict and understand global and local reactivity properties of newly synthesized derivatives. DFT calculations covered fundamental reactivity descriptors such as molecular electrostatic potential and average local ionization energies. Nitrogen atom and benzene rings have been recognized as the most important molecular sites from these aspects. Additionally, to predict whether studied compounds are stable towards the autoxidation mechanism, we have also studied the bond dissociation energies for hydrogen abstraction and identified the derivative which might form potentially genotoxic impurities. Interactions with water, including both global and local aspects, have been covered thanks to the MD simulations and calculations of interaction energies with water, counting of formed hydrogen interactions, and radial distribution functions. MD simulations were also used to identify which excipient could be used together with these compounds, and it has been established that the polyvinylpyrrolidone polymer could be highly compatible with these compounds, from the aspect of calculated solubility parameters.

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Tumoricidal Potential of Novel Amino-1,10-phenanthroline Derived Imine Ligands: Chemical Preparation, Structure, and Biological Investigations

Molecules ◽

10.3390/molecules25122865 ◽

2020 ◽

Vol 25 (12) ◽

pp. 2865

Author(s):

Kollur Shiva Prasad ◽

Renjith Raveendran Pillai ◽

Chandan Shivamallu ◽

Shashanka K. Prasad ◽

Anisha S. Jain ◽

...

Keyword(s):

Dft Calculations ◽

Cell Lines ◽

Density Functional ◽

Computational Analysis ◽

Md Simulations ◽

Distribution Functions ◽

Ic50 Values ◽

Hct 116 ◽

Mcf 7

Herein we report the synthesis and structural elucidation of two novel imine-based ligands, 2-(1,10-phenanthrolin-5-yl)imino)methyl)-5-bromophenol (PIB) and N-(1,10-phenanthrolin-5-yl)-1-(thiophen-3-yl)methanimine (PTM) ligands. An in vitro cytotoxicity assay of the synthesized molecules was carried out against breast, cervical, colorectal, and prostate cancer cell lines as well as immortalized human keratinocytes. The observations indicated that both the molecules possesses dose-dependent selective cytotoxicity of cancer cells with no detrimental effect on the normal cell lines. Furthermore, the detailed computational analysis of newly synthetized ligands (PIB and PTM) has been conducted in order to identify their most important parts from the perspective of local reactivity. The IC50 values of PIB treatment on MCF-7, HeLa, HCT-116 and PC-3 were 15.10, 16.25, 17.88, 17.55 and 23.86 micromoles, respectively. Meanwhile, the IC50 values of PTM on MCF-7, HeLa, HCT-116, PC-3 and HaCat were observed to be 14.82, 15.03, 17.88, 17.28 and 21.22 micromoles, respectively. For computational analysis, we have employed the combination of Density Functional Theory (DFT) calculations and MD simulations. DFT calculations provided us with information about structure and reactivity descriptors based on the electron distribution. Surfaces of molecular electrostatic potential (MEP) and averaged local ionization energy (ALIE) indicated the sites within studied molecules that are most reactive. These results indicated the importance of nitrogen atoms and OH group. Additionally, the values of bond dissociation for hydrogen abstraction showed that both molecules, especially the PTM, are stable toward the influence of autoxidation mechanism. On the other side, MD simulations gave us an insight how ligands interact with water molecules. Namely, the radial distribution functions (RDF) indicated that the hydrogen atom of the OH group in the case of the PIB has the most pronounced interactions with water.

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Investigation of the reactivity properties of a thiourea derivative with anticancer activity by DFT, MD simulations

10.21203/rs.3.rs-178851/v1 ◽

2021 ◽

Author(s):

Sheena Mary ◽

Y. Shyma Mary ◽

Anna Bielenica ◽

Stevan Armaković ◽

Sanja J. Armaković ◽

...

Keyword(s):

Molecular Dynamics ◽

Density Functional ◽

Spectroscopic Analysis ◽

Md Simulations ◽

Distribution Functions ◽

Solubility Parameters ◽

Functional Theory ◽

Quantum Molecular Descriptors ◽

Combined Application ◽

Local Reactivity

Abstract Spectroscopic analysis of 1-(2-fluorophenyl)-3-[3-(trifluoromethyl)phenyl]thiourea (FPTT) is reported. Experimental and theoretical analysis of FPTT, with Molecular Dynamics (MD) simulations, are reported for finding different parameters like: identification of suitable excipients, interactions with water, and sensitivity towards autoxidation. Molecular dynamics and docking show that FPTT can act as a potential inhibitor for new drug. Additionally, local reactivity, interactivity with water, and compatibility of FPTT molecule with frequently used excipients have been studied by combined application of density functional theory (DFT) and MD simulations. Analysis of local reactivity has been performed based on selected fundamental quantum-molecular descriptors, while interactivity with water was studied by calculations of radial distribution functions (RDFs). Compatibility with excipients has been assessed through calculations of solubility parameters, applying MD simulations.

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Computationally Assisted Design of High Signal-to-Noise Photoinduced Electron Transfer-Based Voltage-Sensitive Dyes

10.26434/chemrxiv.12401753 ◽

2020 ◽

Author(s):

Rishikesh Kulkarni ◽

Anneliese Gest ◽

Chun Kei Lam ◽

Benjamin Raliski ◽

Feroz James ◽

...

Keyword(s):

Electron Transfer ◽

Dft Calculations ◽

Photoinduced Electron Transfer ◽

Density Functional ◽

Embryonic Stem ◽

High Sensitivity ◽

Md Simulations ◽

High Signal ◽

Signal To Noise ◽

Green Fluorescent

<p>High signal-to-noise optical voltage indicators will enable simultaneous interrogation of membrane potential in large ensembles of neurons. However, design principles for voltage sensors with high sensitivity and brightness remain elusive, limiting the applicability of voltage imaging. In this paper, we use molecular dynamics (MD) simulations and density functional theory (DFT) calculations to guide the design of a bright and sensitive green-fluorescent voltage-sensitive fluorophore, or VoltageFluor (VF dye), that uses photoinduced electron transfer (PeT) as a voltage-sensing mechanism. MD simulations predict an 11% increase in sensitivity due to membrane orientation, while DFT calculations predict an increase in fluorescence quantum yield, but a decrease in sensitivity due to a decrease in rate of PeT. We confirm these predictions by synthesizing a new VF dye and demonstrating that it displays the expected improvements by doubling the brightness and retaining similar sensitivity to prior VF dyes. Combining theoretical predictions and experimental validation has resulted in the synthesis of the highest signal-to-noise green VF dye to date. We use this new voltage indicator to monitor the electrophysiological maturation of human embryonic stem cell-derived medium spiny neurons. </p>

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Spectroscopic investigations and DFT studies of synthesized 4-acetamidophenyl 3,4,5-trimethoxybenzoate and 4-acetyl phenyl 3,4,5-trimethoxybenzoate a novel conjugate of gallic acid

Letters in Organic Chemistry ◽

10.2174/1570178617999200818205347 ◽

2020 ◽

Vol 17 ◽

Author(s):

Sangeeta Srivastava ◽

Nadeem Ahmad Ansari ◽

Sadaf Aleem

Keyword(s):

Gallic Acid ◽

Density Functional ◽

Energy Gap ◽

Basis Set ◽

Major Constituent ◽

Orbital Energy ◽

Reactivity Descriptors ◽

Homo And Lumo ◽

Electrophilic Reactivity ◽

Global And Local

: Gallic acid is abundantly found in amla (Phyllanthus emblica), a deciduous of the family phyllanthaceae. Gallic acid, the major constituent of the plant was methylated to 3,4,5 trimethoxy gallic acid, which then underwent steglich esterification first with paracetamol and then with 4-hydroxy acetophenone to yield 4-acetamidophenyl 3,4,5-trimethoxybenzoate and 4-acetyl phenyl 3,4,5-trimethoxybenzoate “respectively”. 1H NMR, 13C NMR, UV, FT-IR and mass spectroscopy were used to characterize the synthesized compounds. Density functional theory (B3YLP) using 6-31G (d,p) basis set have been used for quantum chemical calculations. AIM (Atom in molecule) approach depicted weak molecular interactions within the molecules whereas the reactive site and reactivity within the molecule were examined by global and local reactivity descriptors. The HOMO and LUMO energies and frontier orbital energy gap were calculated by time dependant DFT approach using IEFPCM model. Small value for HOMO–LUMO energy gap indicated that easier charge transfer occurs within compound 4. The nucleophilic and electrophilic reactivity were determined by MEP (molecular electrostatic potential) experiment. Polarizability, dipole moment, and first hyperpolarizability values were calculated to depict the NLO (nonlinear optical) property of both the synthesized compounds. The antimicrobial activity was also carried out and broad spectrum antibacterial activity against several strains of bacteria and certain unicellular fungi were exhibited by synthesized compound 3.

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A Molecular Model of PEMFC Catalyst Layer: Simulation on Reactant Transport and Thermal Conduction

Membranes ◽

10.3390/membranes11020148 ◽

2021 ◽

Vol 11 (2) ◽

pp. 148

Author(s):

Wenkai Wang ◽

Zhiguo Qu ◽

Xueliang Wang ◽

Jianfei Zhang

Keyword(s):

Thermal Conductivity ◽

Proton Exchange Membrane ◽

Molecular Model ◽

Phase Interface ◽

Catalyst Layer ◽

Md Simulations ◽

Distribution Functions ◽

Proton Exchange ◽

Pt Catalyst ◽

Reaction Efficiency

Minimizing platinum (Pt) loading while reserving high reaction efficiency in the catalyst layer (CL) has been confirmed as one of the key issues in improving the performance and application of proton exchange membrane fuel cells (PEMFCs). To enhance the reaction efficiency of Pt catalyst in CL, the interfacial interactions in the three-phase interface, i.e., carbon, Pt, and ionomer should be first clarified. In this study, a molecular model containing carbon, Pt, and ionomer compositions is built and the radial distribution functions (RDFs), diffusion coefficient, water cluster morphology, and thermal conductivity are investigated after the equilibrium molecular dynamics (MD) and nonequilibrium MD simulations. The results indicate that increasing water content improves water aggregation and cluster interconnection, both of which benefit the transport of oxygen and proton in the CL. The growing amount of ionomer promotes proton transport but generates additional resistance to oxygen. Both the increase of water and ionomer improve the thermal conductivity of the C. The above-mentioned findings are expected to help design catalyst layers with optimized Pt content and enhanced reaction efficiency, and further improve the performance of PEMFCs.

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Understanding delivery and adsorption of Flutamide drug with ZnONS based on: Dispersion-corrected DFT calculations and MD simulations

Physica E Low-dimensional Systems and Nanostructures ◽

10.1016/j.physe.2021.114937 ◽

2021 ◽

pp. 114937

Author(s):

P. Niknam ◽

S. Jamehbozorgi ◽

M. Rezvani ◽

V. Izadkhah

Keyword(s):

Dft Calculations ◽

Md Simulations

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Making high-dimensional molecular distribution functions tractable through Belief Propagation on Factor Graphs

10.1101/2021.06.28.450193 ◽

2021 ◽

Author(s):

Zachary Smith ◽

Pratyush Tiwary

Keyword(s):

Belief Propagation ◽

Conformational Dynamics ◽

Joint Probability ◽

Md Simulations ◽

Distribution Functions ◽

Factor Graph ◽

High Dimensional ◽

Enhanced Sampling ◽

Small Peptides ◽

Approximate Probability

Molecular dynamics (MD) simulations provide a wealth of high-dimensional data at all-atom and femtosecond resolution but deciphering mechanistic information from this data is an ongoing challenge in physical chemistry and biophysics. Theoretically speaking, joint probabilities of the equilibrium distribution contain all thermodynamic information, but they prove increasingly difficult to compute and interpret as the dimensionality increases. Here, inspired by tools in probabilistic graphical modeling, we develop a factor graph trained through belief propagation that helps factorize the joint probability into an approximate tractable form that can be easily visualized and used. We validate the study through the analysis of the conformational dynamics of two small peptides with 5 and 9 residues. Our validations include testing the conditional dependency predictions through an intervention scheme inspired by Judea Pearl. Secondly we directly use the belief propagation based approximate probability distribution as a high-dimensional static bias for enhanced sampling, where we achieve spontaneous back-and-forth motion between metastable states that is up to 350 times faster than unbiased MD. We believe this work opens up useful ways to thinking about and dealing with high-dimensional molecular simulations.

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Assessment of the KID Procedure on a Mo–oxo Complex, an Open–Shell System

10.20944/preprints202007.0742.v1 ◽

2020 ◽

Author(s):

Jorge Martínez-Araya ◽

Daniel Glossman-Mitnik

Keyword(s):

Density Functional ◽

Organic Molecules ◽

Open Shell ◽

Density Functionals ◽

Functional Theory ◽

Reactivity Descriptors ◽

Shell System ◽

Global And Local ◽

First Time ◽

Local Reactivity Descriptors

The KID (Koopmans in DFT) procedure usually applies in organic molecules of the closed–shell type. We used the KID procedure in an open–shell system for the first time to choose the most suitable density functional to compute global and local reactivity descriptors coming from the Conceptual Density–Functional Theory. From a set of 18 density functionals spread from the second until the fourth rung of the Jacob’s ladder: BP86, B97-D, BLYP, CAM-B3LYP, M06-L, M11-L, MN12-L, B3LYP, PBE0, N12-SX, M06-2X, M11, MN12-SX, CAM-B3LYP, LC-ωHPBE, ωB97X-D, APFD, MN15 and MN15-L, we concluded that CAM-B3LYP provides the best outcome.

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Polydopamine and eumelanin molecular structures investigated with ab initio calculations

Chemical Science ◽

10.1039/c6sc04692d ◽

2017 ◽

Vol 8 (2) ◽

pp. 1631-1641 ◽

Cited By ~ 67

Author(s):

Chun-Teh Chen ◽

Francisco J. Martin-Martinez ◽

Gang Seob Jung ◽

Markus J. Buehler

Keyword(s):

Molecular Dynamics ◽

Density Functional Theory ◽

Dft Calculations ◽

Ab Initio Calculations ◽

Ab Initio ◽

Density Functional ◽

Md Simulations ◽

Molecular Structures ◽

Brute Force ◽

Functional Theory

A set of computational methods that contains a brute-force algorithmic generation of chemical isomers, molecular dynamics (MD) simulations, and density functional theory (DFT) calculations is reported and applied to investigate nearly 3000 probable molecular structures of polydopamine (PDA) and eumelanin.

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