Rational design of selective HDAC2 inhibitors for liver cancer treatment: computational insights into the selectivity mechanism through molecular dynamics simulations and QM/MM calculation

2021 ◽  
Author(s):  
Ye Yang ◽  
Baichun Hu ◽  
Yi Yang ◽  
Kaihua Gong ◽  
Huibin Wang ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Liver Cancer ◽  
Cancer Treatment ◽  
Molecular Dynamics Simulations ◽  
Histone Deacetylase ◽  
Rational Design ◽  
Therapeutic Treatment ◽  
Histone Deacetylase 2 ◽  
Dynamics Simulations

The rational design of selective histone deacetylase 2 (HDAC2) inhibitors is beneficial for the therapeutic treatment of liver cancer, though HDAC2 is highly homologous to HDAC8, which may lead to...

scholarly journals VIRTUAL SCREENING AND MOLECULAR DYNAMICS SIMULATION OF COMPOUNDS FROM THE HERBAL DATABASE OF INDONESIA AGAINST HISTONE DEACETYLASE 2

2018 ◽  
Vol 10 (1) ◽  
pp. 235
Author(s):  
Muhammad Teguh Setiawan ◽  
Arry Yanuar
Keyword(s):  
Molecular Dynamics ◽  
Virtual Screening ◽  
Molecular Dynamics Simulations ◽  
Histone Deacetylase ◽  
Simulation Analysis ◽  
Positive Control ◽  
Dynamics Simulation ◽  
Screening Process ◽  
Histone Deacetylase 2 ◽  
Dynamics Simulations

Objective: This study aimed to find the herbal compounds from the database of Indonesian herbs with potential for use as histone deacetylase 2 (HDAC2)enzyme inhibitors through virtual screening using the LigandScout program.Methods: Virtual screening was conducted using LigandScout 4.09.3, AutodockZN, and AutoDockTools.Results: The virtual screening process resulted in 10 compounds with the highest pharmacophore fit score rating, from which five compounds withthe best criteria for molecular dynamics simulations were selected: Boesenbergin B, pongachalcone I, 6,8-diprenylgenistein, marmin, and mangostin.The ΔG values obtained were, respectively, −8.28, −9.15, −7.05, −9.07, and −7.15. The active crystal ligand N-(2-aminophenyl) benzamide was used asa positive control, with ΔG value of −10.27. Molecular dynamic’s simulations showed that the activity of HDAC2 inhibitors was known to interact inthe amino acid residues His145C, Tyr308C, Zn379C, Leu276C, Phe155C, Phe210C, Leu144C, and Met35C.Conclusions: Based on virtual screening and the molecular dynamics simulations, marmin was considered to provide the best overall activity ofanalysis. Simulation analysis of molecular dynamics from hits compound showed that analysis with MMGBSA gave higher free energy binding valuethan MMPBSA.

Rational design of the survivin/CDK4 complex by combining protein–protein docking and molecular dynamics simulations

2012 ◽  
Vol 19 (4) ◽  
pp. 1507-1514 ◽  
Author(s):  
Jana Selent ◽  
Agnieszka A. Kaczor ◽  
Ramon Guixà-González ◽  
Pau Carrió ◽  
Manuel Pastor ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Rational Design ◽  
Protein Docking ◽  
Dynamics Simulations

Molecular dynamics simulations to aid the rational design of organic friction modifiers

2006 ◽  
Vol 25 (4) ◽  
pp. 495-506 ◽  
Author(s):  
J.E. Davidson ◽  
S.L. Hinchley ◽  
S.G. Harris ◽  
A. Parkin ◽  
S. Parsons ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Rational Design ◽  
Friction Modifiers ◽  
Dynamics Simulations

scholarly journals Accelerating the Discovery of the Beyond Rule of Five Compounds That Have High Affinities Toward SARS-CoV-2 Spike RBD

2021 ◽  
Author(s):  
Abd Al-Aziz Abu-Saleh ◽  
Arpita Yadav ◽  
Raymond A. Poirier
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Rational Design ◽  
De Novo ◽  
Focal Point ◽  
Docking Studies ◽  
Global Pandemic ◽  
Approved Drugs ◽  
Dynamics Simulations ◽  
Binding Energy Calculations

The battle against SARS-CoV-2 coronavirus is the focal point for the global pandemic that has affected millions of lives worldwide. The need for effective and selective therapeutics for the treatment of the disease caused by SARS-CoV-2 is critical. Herein, we performed computational de novo design incorporating molecular docking studies, molecular dynamics simulations, absolute binding energy calculations, and steered molecular dynamics simulations for the discovery of potential compounds with high affinity towards SARS-CoV-2 spike RBD. By leveraging ZINC15 database, a total of 1282 in-clinical and FDA approved drugs were filtered out from nearly 0.5 million protomers of relatively large compounds (MW > 500, and LogP ≤ 5). Our results depict plausible mechanistic aspects related to the blockage of SARS-CoV-2 spike RBD by the top hits discovered. We found that the most promising candidates, namely, ZINC95628821, ZINC95617623, and ZINC261494658, strongly bind to the spike RBD and interfere with the human ACE2 receptor. These findings accelerate the rational design of selective inhibitors targeting the spike RBD protein of SARS-CoV-2.

scholarly journals Rational Design of Thermostable Carbonic Anhydrase Mutants Using Molecular Dynamics Simulations

2018 ◽  
Vol 122 (36) ◽  
pp. 8526-8536 ◽  
Author(s):  
Ricardo Parra-Cruz ◽  
Christof M. Jäger ◽  
Phei Li Lau ◽  
Rachel L. Gomes ◽  
Anca Pordea
Keyword(s):  
Molecular Dynamics ◽  
Carbonic Anhydrase ◽  
Molecular Dynamics Simulations ◽  
Rational Design ◽  
Dynamics Simulations

Rational design of novel fluorescent analogues of cholesterol: a “step-by-step” computational study

2019 ◽  
Vol 21 (28) ◽  
pp. 15487-15503 ◽  
Author(s):  
Andrea Bonvicini ◽  
Peter Reinholdt ◽  
Vincent Tognetti ◽  
Laurent Joubert ◽  
Daniel Wüstner ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Quantum Chemical ◽  
Rational Design ◽  
State Of The Art ◽  
Computational Study ◽  
Dynamics Simulations ◽  
Fluorescent Analogues

State-of-the-art quantum chemical and molecular dynamics simulations are used as guidelines in design of novel fluorescent analogues of cholesterol.

scholarly journals The flexibility of ACE2 in the context of SARS-CoV-2 infection

2020 ◽  
Author(s):  
E. P. Barros ◽  
L. Casalino ◽  
Z. Gaieb ◽  
A. C. Dommer ◽  
Y. Wang ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Receptor Binding ◽  
Rational Design ◽  
Binding Domain ◽  
Full Length ◽  
Receptor Binding Domain ◽  
Spike Glycoprotein ◽  
Linker Region ◽  
Dynamics Simulations

AbstractThe COVID-19 pandemic has swept over the world in the past months, causing significant loss of life and consequences to human health. Although numerous drug and vaccine developments efforts are underway, many questions remain outstanding on the mechanism of SARS-CoV-2 viral association to angiotensin-converting enzyme 2 (ACE2), its main host receptor, and entry in the cell. Structural and biophysical studies indicate some degree of flexibility in the viral extracellular Spike glycoprotein and at the receptor binding domain-receptor interface, suggesting a role in infection. Here, we perform all-atom molecular dynamics simulations of the glycosylated, full-length membrane-bound ACE2 receptor, in both an apo and spike receptor binding domain (RBD) bound state, in order to probe the intrinsic dynamics of the ACE2 receptor in the context of the cell surface. A large degree of fluctuation in the full length structure is observed, indicating hinge bending motions at the linker region connecting the head to the transmembrane helix, while still not disrupting the ACE2 homodimer or ACE2-RBD interfaces. This flexibility translates into an ensemble of ACE2 homodimer conformations that could sterically accommodate binding of the spike trimer to more than one ACE2 homodimer, and suggests a mechanical contribution of the host receptor towards the large spike conformational changes required for cell fusion. This work presents further structural and functional insights into the role of ACE2 in viral infection that can be exploited for the rational design of effective SARS-CoV-2 therapeutics.Statement of SignificanceAs the host receptor of SARS-CoV-2, ACE2 has been the subject of extensive structural and antibody design efforts in aims to curtail COVID-19 spread. Here, we perform molecular dynamics simulations of the homodimer ACE2 full-length structure to study the dynamics of this protein in the context of the cellular membrane. The simulations evidence exceptional plasticity in the protein structure due to flexible hinge motions in the head-transmembrane domain linker region and helix mobility in the membrane, resulting in a varied ensemble of conformations distinct from the experimental structures. Our findings suggest a dynamical contribution of ACE2 to the spike glycoprotein shedding required for infection, and contribute to the question of stoichiometry of the Spike-ACE2 complex.

Sign in / Sign up

Export Citation Format

Share Document