Exploring Aurone Derivatives as Potential Human Pancreatic Lipase Inhibitors through Molecular Docking and Molecular Dynamics Simulations

Inhibition of human pancreatic lipase, a crucial enzyme in dietary fat digestion and absorption, is a potent therapeutic approach for obesity treatment. In this study, human pancreatic lipase inhibitory activity of aurone derivatives was explored by molecular modeling approaches. The target protein was human pancreatic lipase (PDB ID: 1LPB). The 3D structures of 82 published bioactive aurone derivatives were docked successfully into the protein catalytic active site, using AutoDock Vina 1.5.7.rc1. Of them, 62 compounds interacted with the key residues of catalytic trial Ser152-Asp176-His263. The top hit compound (A14), with a docking score of −10.6 kcal⋅mol−1, was subsequently submitted to molecular dynamics simulations, using GROMACS 2018.01. Molecular dynamics simulation results showed that A14 formed a stable complex with 1LPB protein via hydrogen bonds with important residues in regulating enzyme activity (Ser152 and Phe77). Compound A14 showed high potency for further studies, such as the synthesis, in vitro and in vivo tests for pancreatic lipase inhibitory activity.

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Interaction of the TonB dependent transporter HasR with its cognate TonB-like protein HasB in a membrane environment

10.1101/2021.04.21.440789 ◽

2021 ◽

Author(s):

Kamolrat Somboon ◽

Oliver Melling ◽

Maylis Lejeune ◽

Glaucia M.S. Pinheiro ◽

Annick Paquelin ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Protein Dynamics ◽

Periplasmic Space ◽

Geometrical Constraints ◽

Flexible Region ◽

Tonb Protein ◽

Dynamics Simulations

Energized nutrient import in bacteria needs the interaction between a TonB-dependent transporter (TBDT) and a TonB protein. The mechanism of energy and signal transfer between these two proteins is not well understood. They belong to two membranes separated by the periplasmic space and possess each a disordered and flexible region. Therefore, the membranes, their distance and geometrical constraints together with the protein dynamics are important factors for deciphering this trans-envelope system. Here we report the first example of the interaction of a TBDT with a TonB protein in the presence of both membranes. By combining molecular dynamics simulations in a membrane model, in vitro and in vivo phenotypic experiments we obtained the comprehensive network of interaction between HasR, a heme/hemophore receptor and its dedicated TonB protein, HasB.

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Virtual Screening of Phytochemicals by Targeting HR1 Domain of SARS-CoV-2 S Protein: Molecular Docking, Molecular Dynamics Simulations, and DFT Studies

BioMed Research International ◽

10.1155/2021/6661191 ◽

2021 ◽

Vol 2021 ◽

pp. 1-19

Author(s):

Arshia Majeed ◽

Waqar Hussain ◽

Farkhanda Yasmin ◽

Ammara Akhtar ◽

Nouman Rasool

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Molecular Dynamics Simulations ◽

Density Functional ◽

Spike Protein ◽

Effective Vaccine ◽

High Morbidity ◽

Dynamics Simulations

The recent COVID-19 pandemic has impacted nearly the whole world due to its high morbidity and mortality rate. Thus, scientists around the globe are working to find potent drugs and designing an effective vaccine against COVID-19. Phytochemicals from medicinal plants are known to have a long history for the treatment of various pathogens and infections; thus, keeping this in mind, this study was performed to explore the potential of different phytochemicals as candidate inhibitors of the HR1 domain in SARS-CoV-2 spike protein by using computer-aided drug discovery methods. Initially, the pharmacological assessment was performed to study the drug-likeness properties of the phytochemicals for their safe human administration. Suitable compounds were subjected to molecular docking to screen strongly binding phytochemicals with HR1 while the stability of ligand binding was analyzed using molecular dynamics simulations. Quantum computation-based density functional theory (DFT) analysis was constituted to analyze the reactivity of these compounds with the receptor. Through analysis, 108 phytochemicals passed the pharmacological assessment and upon docking of these 108 phytochemicals, 36 were screened passing a threshold of -8.5 kcal/mol. After analyzing stability and reactivity, 5 phytochemicals, i.e., SilybinC, Isopomiferin, Lycopene, SilydianinB, and Silydianin are identified as novel and potent candidates for the inhibition of HR1 domain in SARS-CoV-2 spike protein. Based on these results, it is concluded that these compounds can play an important role in the design and development of a drug against COVID-19, after an exhaustive in vitro and in vivo examination of these compounds, in future.

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Discovery of Novel Tankyrase Inhibitors through Molecular Docking-Based Virtual Screening and Molecular Dynamics Simulation Studies

Molecules ◽

10.3390/molecules25143171 ◽

2020 ◽

Vol 25 (14) ◽

pp. 3171 ◽

Cited By ~ 4

Author(s):

Vladimir P. Berishvili ◽

Alexander N. Kuimov ◽

Andrew E. Voronkov ◽

Eugene V. Radchenko ◽

Pradeep Kumar ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Virtual Screening ◽

Molecular Dynamics Simulations ◽

Binding Energies ◽

Dynamics Simulation ◽

Ic50 Values ◽

Energy Perturbation ◽

Dynamics Simulations

Tankyrase enzymes (TNKS), a core part of the canonical Wnt pathway, are a promising target in the search for potential anti-cancer agents. Although several hundreds of the TNKS inhibitors are currently known, identification of their novel chemotypes attracts considerable interest. In this study, the molecular docking and machine learning-based virtual screening techniques combined with the physico-chemical and ADMET (absorption, distribution, metabolism, excretion, toxicity) profile prediction and molecular dynamics simulations were applied to a subset of the ZINC database containing about 1.7 M commercially available compounds. Out of seven candidate compounds biologically evaluated in vitro for their inhibition of the TNKS2 enzyme using immunochemical assay, two compounds have shown a decent level of inhibitory activity with the IC50 values of less than 10 nM and 10 μM. Relatively simple scores based on molecular docking or MM-PBSA (molecular mechanics, Poisson-Boltzmann, surface area) methods proved unsuitable for predicting the effect of structural modification or for accurate ranking of the compounds based on their binding energies. On the other hand, the molecular dynamics simulations and Free Energy Perturbation (FEP) calculations allowed us to further decipher the structure-activity relationships and retrospectively analyze the docking-based virtual screening performance. This approach can be applied at the subsequent lead optimization stages.

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Conserved α-helix-3 is crucial for structure and functions of Rad6 E2 ubiquitin-conjugating enzymes

10.1101/2021.10.12.464121 ◽

2021 ◽

Author(s):

Prakash K. Shukla ◽

Dhiraj Sinha ◽

Andrew M. Leng ◽

Jesse E. Bissell ◽

Shravya Thatipamula ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Biological Functions ◽

Conjugating Enzymes ◽

Α Helix ◽

Dynamics Simulations ◽

Ubiquitin Conjugating Enzymes ◽

Structure And Activity

AbstractRad6, an E2 ubiquitin-conjugating enzyme conserved from yeast to humans, functions in transcription, genome maintenance and proteostasis. The contributions of many conserved secondary structures of Rad6 and its human homologs UBE2A and UBE2B to their biological functions are not understood. A mutant RAD6 allele with a missense substitution at alanine-126 (A126) of α-helix-3 that causes defects in telomeric gene silencing, DNA repair and protein degradation was reported over two decades ago. Here, using a combination of genetics, biochemical, biophysical, and computational approaches, we discovered that α-helix-3 A126 mutations compromise the ability of Rad6 to ubiquitinate target proteins without disrupting interactions with partner E3 ubiquitin-ligases that are required for their various biological functions in vivo. Explaining the defective in vitro or in vivo ubiquitination activities, molecular dynamics simulations and NMR showed that α-helix-3 A126 mutations cause local disorder of the catalytic pocket of Rad6, and also disorganize the global structure of the protein to decrease its stability in vivo. We further demonstrate that α-helix-3 A126 mutations deform the structures of UBE2A and UBE2B, the human Rad6 homologs, and compromise the in vitro ubiquitination activity and folding of UBE2B. Molecular dynamics simulations and circular dichroism spectroscopy along with functional studies further revealed that cancer-associated mutations in α-helix-3 of UBE2A or UBE2B alter both structure and activity, providing an explanation for their pathogenicity. Overall, our studies reveal that the conserved α-helix-3 is a crucial structural constituent that controls the organization of catalytic pockets and biological functions of the Rad6-family E2 ubiquitin-conjugating enzymes.HighlightsContributions of the conserved α-helix-3 to the functions of E2 enzymes is not known.Mutations in alanine-126 of α-helix-3 impair in vitro enzymatic activity and in vivo biological functions of Rad6.Mutations in alanine-126 of α-helix-3 disorganize local or global protein structure, compromise folding or stability, and impair the catalytic activities of yeast Rad6 and its human homologs UBE2A and UBE2B.Cancer-associated mutations in α-helix-3 of human UBE2A or UBE2B alter protein flexibility, structure, and activity.α-helix-3 is a key structural component of yeast and human Rad6 E2 ubiquitin-conjugating enzymes.

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Molecular Basis of Iterative C–H Oxidation by TamI, a Multifunctional P450 Monooxygenase from the Tirandamycin Biosynthetic Pathway

10.26434/chemrxiv.12710159.v1 ◽

2020 ◽

Author(s):

Sean A. Newmister ◽

Kinshuk Raj Srivastava ◽

Rosa V. Espinoza ◽

Kersti Caddell Haatveit ◽

Yogan Khatri ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Molecular Basis ◽

Hydrophobic Interactions ◽

Cytochromes P450 ◽

Targeted Mutagenesis ◽

P450 Monooxygenase ◽

Bond Functionalization ◽

Dynamics Simulations

Biocatalysis offers an expanding and powerful strategy to construct and diversify complex molecules by C-H bond functionalization. Due to their high selectivity, enzymes have become an essential tool for C-H bond functionalization and offer complementary reactivity to small-molecule catalysts. Hemoproteins, particularly cytochromes P450, have proven effective for selective oxidation of unactivated C-H bonds. Previously, we reported the in vitro characterization of an oxidative tailoring cascade in which TamI, a multifunctional P450 functions co-dependently with the TamL flavoprotein to catalyze regio- and stereoselective hydroxylations and epoxidation to yield tirandamycin A and tirandamycin B. TamI follows a defined order including 1) C10 hydroxylation, 2) C11/C12 epoxidation, and 3) C18 hydroxylation. Here we present a structural, biochemical, and computational investigation of TamI to understand the molecular basis of its substrate binding, diverse reactivity, and specific reaction sequence. The crystal structure of TamI in complex with tirandamycin C together with molecular dynamics simulations and targeted mutagenesis suggest that hydrophobic interactions with the polyene chain of its natural substrate are critical for molecular recognition. QM/MM calculations and molecular dynamics simulations of TamI with variant substrates provided detailed information on the molecular basis of sequential reactivity, and pattern of regio- and stereo-selectivity in catalyzing the three-step oxidative cascade.<br>

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Reactive molecular dynamics simulation of the high-temperature pyrolysis of 2,2′,2′′,4,4′,4′′,6,6′,6′′-nonanitro-1,1′:3′,1′′-terphenyl (NONA)

RSC Advances ◽

10.1039/c9ra10261b ◽

2020 ◽

Vol 10 (9) ◽

pp. 5507-5515

Author(s):

Liang Song ◽

Feng-Qi Zhao ◽

Si-Yu Xu ◽

Xue-Hai Ju

Keyword(s):

Molecular Dynamics ◽

High Temperature ◽

Molecular Dynamics Simulation ◽

Molecular Dynamics Simulations ◽

Dynamics Simulation ◽

Reactive Molecular Dynamics ◽

Ring Compounds ◽

Fused Ring ◽

Dynamics Simulations

The bimolecular and fused ring compounds are found in the high-temperature pyrolysis of NONA using ReaxFF molecular dynamics simulations.

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Investigation of the inhibitory activity of some dietary bioactive flavonoids against SARS-CoV-2 using molecular dynamics simulations and MM-PBSA calculations

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2021.1891139 ◽

2021 ◽

pp. 1-16

Author(s):

Jibin K. Varughese ◽

K. L. Joseph Libin ◽

K. S. Sindhu ◽

A. V. Rosily ◽

T. G. Abi

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Inhibitory Activity ◽

Dynamics Simulations

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Protein folding: Molecular dynamics simulations and in vitro studies for probing mechanism of urea- and guanidinium chloride-induced unfolding of horse cytochrome-c

International Journal of Biological Macromolecules ◽

10.1016/j.ijbiomac.2018.10.186 ◽

2019 ◽

Vol 122 ◽

pp. 695-704 ◽

Cited By ~ 8

Author(s):

Sabab Hasan Khan ◽

Amresh Prakash ◽

Preeti Pandey ◽

Andrew M. Lynn ◽

Asimul Islam ◽

...

Keyword(s):

Molecular Dynamics ◽

Protein Folding ◽

Cytochrome C ◽

Molecular Dynamics Simulations ◽

In Vitro Studies ◽

Guanidinium Chloride ◽

Dynamics Simulations ◽

Horse Cytochrome

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An Analysis Based on Molecular Docking and Molecular Dynamics Simulation Study of Bromelain as Anti-SARS-CoV-2 Variants

Frontiers in Pharmacology ◽

10.3389/fphar.2021.717757 ◽

2021 ◽

Vol 12 ◽

Cited By ~ 1

Author(s):

Trina Ekawati Tallei ◽

Fatimawali ◽

Afriza Yelnetty ◽

Rinaldi Idroes ◽

Diah Kusumawaty ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Molecular Dynamics Simulation ◽

Three Dimensional ◽

Md Simulations ◽

Inhibitory Effect ◽

Dynamics Simulation ◽

Novel Coronavirus

The rapid spread of a novel coronavirus known as SARS-CoV-2 has compelled the entire world to seek ways to weaken this virus, prevent its spread and also eliminate it. However, no drug has been approved to treat COVID-19. Furthermore, the receptor-binding domain (RBD) on this viral spike protein, as well as several other important parts of this virus, have recently undergone mutations, resulting in new virus variants. While no treatment is currently available, a naturally derived molecule with known antiviral properties could be used as a potential treatment. Bromelain is an enzyme found in the fruit and stem of pineapples. This substance has been shown to have a broad antiviral activity. In this article, we analyse the ability of bromelain to counteract various variants of the SARS-CoV-2 by targeting bromelain binding on the side of this viral interaction with human angiotensin-converting enzyme 2 (hACE2) using molecular docking and molecular dynamics simulation approaches. We have succeeded in making three-dimensional configurations of various RBD variants using protein modelling. Bromelain exhibited good binding affinity toward various variants of RBDs and binds right at the binding site between RBDs and hACE2. This result is also presented in the modelling between Bromelain, RBD, and hACE2. The molecular dynamics (MD) simulations study revealed significant stability of the bromelain and RBD proteins separately up to 100 ns with an RMSD value of 2 Å. Furthermore, despite increases in RMSD and changes in Rog values of complexes, which are likely due to some destabilized interactions between bromelain and RBD proteins, two proteins in each complex remained bonded, and the site where the two proteins bind remained unchanged. This finding indicated that bromelain could have an inhibitory effect on different SARS-CoV-2 variants, paving the way for a new SARS-CoV-2 inhibitor drug. However, more in vitro and in vivo research on this potential mechanism of action is required.

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