Structural Insight into the Interactions between Structurally Similar Inhibitors and SIRT6

Sirtuin 6 (SIRT6) is an NAD+-dependent deacetylase with a significant role in 20% of all cancers, such as colon cancers and rectal adenocarcinoma. However, there is currently no effective drug for cancers related to SIRT6. To explore potential inhibitors of SIRT6, it is essential to reveal details of the interaction mechanisms between inhibitors and SIRT6 at the atomic level. The nature of small molecules from herbs have many advantages as inhibitors. Based on the conformational characteristics of the inhibitor Compound 9 (Asinex ID: BAS13555470), we explored the natural molecule Scutellarin, one compound of Huang Qin, which is an effective herb for curing cancer that has been described in the Traditional Chinese Medicine (TCMS) library. We investigated the interactions between SIRT6 and the inhibitors using molecular dynamics (MD) simulations. We illustrated that the structurally similar inhibitors have a similar binding mode to SIRT6 with residues—Leu9, Phe64, Val115, His133 and Trp188. Hydrophobic and π-stacking interactions play important roles in the interactions between SIRT6 and inhibitors. In summary, our results reveal the interactive mechanism of SIRT6 and the inhibitors and we also provide Scutellarin as a new potential inhibitor of SIRT6. Our study provides a new potential way to explore potential inhibitors from TCMS.

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Interactive Mechanism of Potential Inhibitors with Glycosyl for SARS-CoV-2 by Molecular Dynamics Simulation

Processes ◽

10.3390/pr9101749 ◽

2021 ◽

Vol 9 (10) ◽

pp. 1749

Author(s):

Yuqi Zhang ◽

Li Chen ◽

Xiaoyu Wang ◽

Yanyan Zhu ◽

Yongsheng Liu ◽

...

Keyword(s):

Molecular Dynamics ◽

Small Molecules ◽

Binding Sites ◽

Md Simulations ◽

Experimental Methods ◽

Dynamics Simulation ◽

Theoretical Research ◽

Stacking Interactions ◽

Receptor Binding Domain ◽

Potential Inhibitors

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a type of Ribonucleic Acid (RNA) coronavirus and it has infected and killed many people around the world. It is reported that the receptor binding domain of the spike protein (S_RBD) of the SARS-CoV-2 virus is responsible for attachment to human angiotensin converting enzyme II (ACE2). Many researchers are attempting to search potential inhibitors for fighting SARS-CoV-2 infection using theoretical or experimental methods. In terms of experimental and theoretical research, Cefuroxime, Erythromycin, Lincomycin and Ofloxacin are the potential inhibitors of SARS-CoV-2. However, the interactive mechanism of the protein SARS-CoV-2 and the inhibitors are still elusive. Here, we investigated the interactions between S_RBD and the inhibitors using molecular dynamics (MD) simulations. Interestingly, we found that there are two binding sites of S_RBD for the four small molecules. In addition, our analysis also illustrated that hydrophobic and π-π stacking interactions play crucial roles in the interactions between S_RBD and the small molecules. In our work, we also found that small molecules with glycosyl group have more effect on the conformation of S_RBD than other inhibitors, and they are also potential inhibitors for the genetic variants of SARS-CoV-2. This study provides in silico-derived mechanistic insights into the interactions of S_RBD and inhibitors, which may provide new clues for fighting SARS-CoV-2 infection.

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Structural insight into the binding mode between the targeting domain of ALE-1 (92AA) and pentaglycine of peptidoglycan

Protein Engineering Design and Selection ◽

10.1093/protein/gzp014 ◽

2009 ◽

Vol 22 (7) ◽

pp. 385-391 ◽

Cited By ~ 8

Author(s):

Hideki Hirakawa ◽

Hidenori Akita ◽

Tamaki Fujiwara ◽

Motoyuki Sugai ◽

Satoru Kuhara

Keyword(s):

Binding Mode ◽

Structural Insight ◽

Insight Into

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Structural Insight into the Binding Mode of FXR and GPBAR1 Modulators

Bile Acids and Their Receptors - Handbook of Experimental Pharmacology ◽

10.1007/164_2019_234 ◽

2019 ◽

pp. 111-136 ◽

Cited By ~ 4

Author(s):

Francesco Saverio Di Leva ◽

Daniele Di Marino ◽

Vittorio Limongelli

Keyword(s):

Binding Mode ◽

Structural Insight ◽

Insight Into

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A structural insight into the P1 S1 binding mode of diaminoethylphosphonic and phosphinic acids, selective inhibitors of alanine aminopeptidases

European Journal of Medicinal Chemistry ◽

10.1016/j.ejmech.2016.04.018 ◽

2016 ◽

Vol 117 ◽

pp. 187-196 ◽

Cited By ~ 22

Author(s):

Ewelina Węglarz-Tomczak ◽

Łukasz Berlicki ◽

Małgorzata Pawełczak ◽

Bogusław Nocek ◽

Andrzej Joachimiak ◽

...

Keyword(s):

Binding Mode ◽

Selective Inhibitors ◽

Phosphinic Acids ◽

Structural Insight ◽

Insight Into

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Virtual Screening and Elucidation of Putative Binding Mode for Small Molecule Antagonist of BCL2 BH4 Domain

10.1101/2020.07.29.226308 ◽

2020 ◽

Author(s):

Ireoluwa Yinka Joel ◽

Temidayo Olamide Adigun ◽

Ahmeedah Ololade Ajibola ◽

Olukayode Olusola Bankole ◽

Ugochukwu Okechukwu Ozojiofor ◽

...

Keyword(s):

Cell Death ◽

Small Molecules ◽

Md Simulations ◽

Binding Mode ◽

Intrinsic Pathway ◽

Bcl2 Family ◽

Small Molecule Antagonist ◽

Electrophilic Reactions ◽

Family Protein ◽

Bcl2 Protein

AbstractEvading apoptosis is a hallmark of cancer cells, therefore therapeutic strategies have been developed to induce cell death. BCL2 family protein governs the intrinsic pathway of cell death. Targeting the BH4 domain to modulate the anti-apoptosis activities of BCL2 protein has been established however, BDA366 is the only BH4 binding molecule to be reported. Virtually screening ~ 1,000,000 compounds 11 putative BH4 binding small molecules with binding affinity ~ −84kcal/mol to - 64kcal/mol resulted. Using QM-polarized docking, Induced-fit docking, and QM-MM optimization, a putative binding mode for the top 3 compounds is proposed: compound 139068 interactions with GLU13, MET16, LYS17, ASP31, and GLU42; compound 138967 interactions with ASP10, ARG12, GLU13, HIS20, MET16, and GLU42; compound 38831 interactions with ASP10, ARG12, GLU13, LYS17, and GLU42. MD simulations (NMA) data showed the binding of the three compounds to be stable with low eigenvalues. Electronic properties derived via DFT calculations suggest chemical reaction of the compounds be via electrophilic reactions.

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Structural insight into binding mode of inhibitor with SAHH of Plasmodium and human: interaction of curcumin with anti-malarial drug targets

Journal of Chemical Biology ◽

10.1007/s12154-016-0155-7 ◽

2016 ◽

Vol 9 (4) ◽

pp. 107-120 ◽

Cited By ~ 8

Author(s):

Dev Bukhsh Singh ◽

Seema Dwivedi

Keyword(s):

Drug Targets ◽

Binding Mode ◽

Human Interaction ◽

Structural Insight ◽

Insight Into

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Prediction of potential inhibitors of the dimeric SARS-CoV-2 main proteinase through the MM/GBSA approach

10.21203/rs.3.rs-21205/v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Martiniano Bello

Keyword(s):

3D Structure ◽

Antiviral Drug ◽

Md Simulations ◽

X Ray Crystallography ◽

Approved Drugs ◽

Potential Inhibitors ◽

Fda Approved Drugs ◽

Insight Into ◽

Hiv 1 ◽

Selection Of

Abstract Since the emergence of SARS-CoV-2, to date, no effective antiviral drug has been approved to treat the disease, and no vaccine against SARS-CoV-2 is available. Under this scenario, the combination of two HIV-1 protease inhibitors, lopinavir and ritonavir, has attracted attention since they have been previously employed against the SARS-CoV main proteinase (Mpro) and exhibited some signs of effectiveness. Recently, the 3D structure of SARS-CoV-2 Mpro was constructed based on the monomeric SARS-CoV Mpro and employed to identify potential FDA-approved small inhibitors against SARS-CoV-2 Mpro, allowing the selection of 15 drugs among 1903 approved drugs to be employed. In this study, we performed docking of these 15 approved drugs against the recently solved X-ray crystallography structure of SARS-CoV-2 Mpro (PDB ID: 6LU7) in the monomeric and dimeric states; the latter is the functional state that was determined in a biological context, and these were submitted for MD simulations coupled with the MM/GBSA approach to obtain insight into the inhibitory activity of these compounds. Similar studies were performed with lopinavir and ritonavir coupled to monomeric and dimeric SARS-CoV Mpro and SARS-CoV-2 Mpro to compare the inhibitory differences. Our study provides the structural and energetic basis of the inhibitory properties of lopinavir and ritonavir on SARS-CoV Mpro and SARS-CoV-2 Mpro, allowing us to identify two FDA-approved drugs that can be used against SARS-CoV-2 Mpro. This study also demonstrated that drug discovery requires the dimeric state to obtain good results.

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Molecular basis of small-molecule binding to α-synuclein

10.1101/2021.01.22.426549 ◽

2021 ◽

Author(s):

Paul Robustelli ◽

Alain Ibanez-de-Opakua ◽

Cecily Campbell-Bezat ◽

Fabrizio Giordanetto ◽

Stefan Becker ◽

...

Keyword(s):

Small Molecules ◽

Small Molecule ◽

Rational Design ◽

Intrinsically Disordered Proteins ◽

Md Simulations ◽

Structural Features ◽

Atomic Level ◽

Disordered Proteins ◽

Structure Based Drug Design ◽

Intrinsically Disordered

AbstractIntrinsically disordered proteins (IDPs) are implicated in many human diseases. They have generally not been amenable to conventional structure-based drug design, however, because their intrinsic conformational variability has precluded an atomic-level understanding of their binding to small molecules. Here we present long-timescale, atomic-level molecular dynamics (MD) simulations of monomeric α-synuclein (an IDP whose aggregation is associated with Parkinson’s disease) binding the small-molecule drug fasudil in which the observed protein-ligand interactions were found to be in good agreement with previously reported NMR chemical shift data. In our simulations, fasudil, when bound, favored certain charge-charge and π-stacking interactions near the C terminus of α-synuclein, but tended not to form these interactions simultaneously, rather breaking one of these interactions and forming another nearby (a mechanism we term dynamic shuttling). Further simulations with small molecules chosen to modify these interactions yielded binding affinities and key structural features of binding consistent with subsequent NMR experiments, suggesting the potential for MD-based strategies to facilitate the rational design of small molecules that bind with disordered proteins.

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