scholarly journals In silico and saturation transfer difference NMR approaches to unravel the binding mode of an andrographolide derivative to K-Ras oncoprotein

2020 ◽  
Vol 12 (18) ◽  
pp. 1611-1631
Author(s):  
Shun Ying Quah ◽  
Michelle Siying Tan ◽  
Kok Lian Ho ◽  
Nizar Abdul Manan ◽  
Alemayehu Abebe Gorfe ◽  
...  
Keyword(s):  
In Silico ◽  
Hydrophobic Interactions ◽  
Binding Pocket ◽  
Binding Mode ◽  
Dynamics Simulation ◽  
Saturation Transfer ◽  
In Silico Docking ◽  
Saturation Transfer Difference ◽  
Major Interest ◽  
Ras Oncoprotein

Background: Andrographolide and its benzylidene derivatives, SRJ09 and SRJ23, potentially bind oncogenic K-Ras to exert anticancer activity. Their molecular interactions with K-Ras oncoproteins that lead to effective biological activity are of major interest. Methods & results: In silico docking and molecular dynamics simulation were performed using Glide and Desmond, respectively; while saturation transfer difference NMR was performed using GDP-bound K-RasG12V. SRJ23 was found to bind strongly and selectively to K-RasG12V, by anchoring to a binding pocket (namely p2) principally via hydrogen bond and hydrophobic interactions. The saturation transfer difference NMR analysis revealed the proximity of protons of functional moieties in SRJ23 to K-RasG12V, suggesting positive binding. Conclusion: SRJ23 binds strongly and interacts stably with K-RasG12V to exhibit its inhibitory activity.

scholarly journals Exploring aromatic cage flexibility of the histone methyllysine reader protein Spindlin1 and its impact on binding mode prediction: an in silico study

2021 ◽  
Author(s):  
Chiara Luise ◽  
Dina Robaa ◽  
Wolfgang Sippl
Keyword(s):  
Molecular Dynamic ◽  
In Silico ◽  
Binding Pocket ◽  
Binding Mode ◽  
Molecular Dynamic Simulations ◽  
Flexible Docking ◽  
Dynamic Simulations ◽  
Binding Mode Prediction ◽  
Aromatic Cage ◽  
The Right

AbstractSome of the main challenges faced in drug discovery are pocket flexibility and binding mode prediction. In this work, we explored the aromatic cage flexibility of the histone methyllysine reader protein Spindlin1 and its impact on binding mode prediction by means of in silico approaches. We first investigated the Spindlin1 aromatic cage plasticity by analyzing the available crystal structures and through molecular dynamic simulations. Then we assessed the ability of rigid docking and flexible docking to rightly reproduce the binding mode of a known ligand into Spindlin1, as an example of a reader protein displaying flexibility in the binding pocket. The ability of induced fit docking was further probed to test if the right ligand binding mode could be obtained through flexible docking regardless of the initial protein conformation. Finally, the stability of generated docking poses was verified by molecular dynamic simulations. Accurate binding mode prediction was obtained showing that the herein reported approach is a highly promising combination of in silico methods able to rightly predict the binding mode of small molecule ligands in flexible binding pockets, such as those observed in some reader proteins.

scholarly journals Pharmacophore Modelling-Based Drug Repurposing Approaches for SARS-CoV-2 Therapeutics

2021 ◽  
Vol 9 ◽  
Author(s):  
Shailima Rampogu ◽  
Keun Woo Lee
Keyword(s):  
Effective Treatment ◽  
Pharmacophore Model ◽  
Drug Repurposing ◽  
Binding Pocket ◽  
Binding Mode ◽  
Computational Method ◽  
Dynamics Simulation ◽  
Potential Candidate ◽  
Pharmacophore Modelling ◽  
Discovery Studio

The recent outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a devastating effect globally with no effective treatment. The swift strategy to find effective treatment against coronavirus disease 2019 (COVID-19) is to repurpose the approved drugs. In this pursuit, an exhaustive computational method has been used on the DrugBank compounds targeting nsp16/nsp10 complex (PDB code: 6W4H). A structure-based pharmacophore model was generated, and the selected model was escalated to screen DrugBank database, resulting in three compounds. These compounds were subjected to molecular docking studies at the protein-binding pocket employing the CDOCKER module available with the Discovery Studio v18. In order to discover potential candidate compounds, the co-crystallized compound S-adenosyl methionine (SAM) was used as the reference compound. Additionally, the compounds remdesivir and hydroxycholoroquine were employed for comparative docking. The results have shown that the three compounds have demonstrated a higher dock score than the reference compounds and were upgraded to molecular dynamics simulation (MDS) studies. The MDS results demonstrated that the three compounds, framycetin, kanamycin, and tobramycin, are promising candidate compounds. They have represented a stable binding mode at the targets binding pocket with an average protein backbone root mean square deviation below 0.3 nm. Additionally, they have prompted the hydrogen bonds during the entire simulations, inferring that the compounds have occupied the active site firmly. Taken together, our findings propose framycetin, kanamycin, and tobramycin as potent putative inhibitors for COVID-19 therapeutics.

scholarly journals Binding Mode Knowledge of New Possible Anti-Hypertensive Compounds Designed In Silico Using Neutral Endopeptidase (NEP) as a Target

2020 ◽  
Author(s):  
Emilio Lamazares ◽  
Yudith Cañizares-Carmenate ◽  
Juan A. Castillo-Garit ◽  
Karel Mena-Ulecia
Keyword(s):  
Arterial Hypertension ◽  
In Silico ◽  
Neutral Endopeptidase ◽  
Binding Mode ◽  
Dynamics Simulation ◽  
Energy Decomposition ◽  
Simulation Tools ◽  
Free Energy Decomposition ◽  
Key Enzyme ◽  
New Compounds

Arterial hypertension is a health problem that affects millions of people around the world. Particularly in Chile, according to the last health survey in 2019, 28.7% of the population had this condition, and arterial hypertension complications cause one in three deaths per year. In this work, we have used molecular simulation tools to evaluate new compounds designed in silico by our group as possible anti-hypertensive agents, taking Neutral Endopeptidase (NEP) as a target, a key enzyme in the arterial hypertension regulation at the level kidney. We use docking experiments, molecular dynamics simulation, free energy decomposition calculations (by MM-PBSA method), and ligand efficiency analysis to identify the best anti-hypertensive agent pharmacokinetic and toxicological predictions (ADME-Tox). The energetic components that contribute to the complexes stability are the electrostatic and Van der Waals components; however, when the ADME-Tox properties were analyzed, we conclude that the best anti-hypertensive candidate agents are Lig783 and Lig3444, taking Neutra Endopeptidase as a target.

scholarly journals Inhibition of Phosphodiesterase 5 Enzyme by Pterine- 6 Carboxylic Acid from Baphia nitida –Related to Erectile Dysfunction: Computational Kinetic

2020 ◽  
pp. 49-55
Author(s):  
Wopara, Iheanyichukwu ◽  
S. K. Mobisson ◽  
Egelege Aziemeola Pius ◽  
A. A. Uwakwe ◽  
M. O. Wegwu
Keyword(s):  
Erectile Dysfunction ◽  
Carboxylic Acid ◽  
Active Site ◽  
In Silico ◽  
Binding Pocket ◽  
Docking Studies ◽  
Drug Candidate ◽  
In Silico Docking ◽  
In Silico Studies ◽  
Phosphodiesterase 5

Treatment of erectile dysfunction is associated with inhibition of Phosphodiesterase 5 enzyme. This study deals with the evaluation of Pterin-6-carboxylic acid inhibitory activity on phosphodiesterase 5 (PDB ID: 4OEW) using in silico docking studies. Pterin-6-carboxylic acid from Baphia nitida was isolated using GC-MS and docked into PDE5 active site. The docking result showed that pterin-6-carboxylic acid bind to the active site of phosphodiesterase 5 with the binding energy value of -7.1 and 2.05A° - 2.23A° when compared with other compound found in the plant. Moreso, docking analysis with the ligand identified specific residues such as: Ile 778, Phe 820, Gln 817, Ser 815 and Gln 775 within the binding pocket which played an important role in the ligand binding affinity to the protein. Result from our In silico studies hypothesized that pterin-6-carboxylic acid can be an inhibitory agent for PDE5 protein which could be a potential drug candidate for the treatment of erectile dysfunction.

scholarly journals Peptide-Protein Interaction Studies of Antimicrobial Peptides Targeting Middle East Respiratory Syndrome Coronavirus Spike Protein: An In Silico Approach

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Sabeena Mustafa ◽  
Hanan Balkhy ◽  
Musa Gabere
Keyword(s):  
Middle East ◽  
Antimicrobial Peptides ◽  
Protein Interactions ◽  
In Silico ◽  
Therapeutic Option ◽  
Binding Mode ◽  
Middle East Respiratory Syndrome ◽  
Spike Protein ◽  
In Silico Docking ◽  
Peptide Database

There is no effective therapeutic or vaccine for Middle East Respiratory Syndrome and this study attempts to find therapy using peptide by establishing a basis for the peptide-protein interactions through in silico docking studies for the spike protein of MERS-CoV. The antimicrobial peptides (AMPs) were retrieved from the antimicrobial peptide database (APD3) and shortlisted based on certain important physicochemical properties. The binding mode of the shortlisted peptides was measured based on the number of clusters which forms in a protein-peptide docking using Piper. As a result, we identified a list of putative AMPs which binds to the spike protein of MERS-CoV, which may be crucial in providing the inhibitory action. It is observed that seven putative peptides have good binding score based on cluster size cutoff of 208. We conclude that seven peptides, namely, AP00225, AP00180, AP00549, AP00744, AP00729, AP00764, and AP00223, could possibly have binding with the active site of the MERS-CoV spike protein. These seven AMPs could serve as a therapeutic option for MERS and enhance its treatment outcome.

Chemical synthesis and characterization of a new quinazolinedione competitive antagonist for strigolactone receptors with an unexpected binding mode

2019 ◽  
Vol 476 (12) ◽  
pp. 1843-1856 ◽  
Author(s):  
Cyril Hamiaux ◽  
Lesley Larsen ◽  
Hui Wen Lee ◽  
Zhiwei Luo ◽  
Prachi Sharma ◽  
...  
Keyword(s):  
In Silico ◽  
Binding Mode ◽  
Crystal Structure Analysis ◽  
Tolfenamic Acid ◽  
In Vitro Assays ◽  
Inhibition Mechanism ◽  
In Planta ◽  
Competitive Antagonist ◽  
In Silico Docking

Abstract Strigolactones (SLs) are multifunctional plant hormones regulating essential physiological processes affecting growth and development. In vascular plants, SLs are recognized by α/β hydrolase-fold proteins from the D14/DAD2 (Dwarf14/Decreased Apical Dominance 2) family in the initial step of the signaling pathway. We have previously discovered that N-phenylanthranilic acid derivatives (e.g. tolfenamic acid) are potent antagonists of SL receptors, prompting us to design quinazolinone and quinazolinedione derivatives (QADs and QADDs, respectively) as second-generation antagonists. Initial in silico docking studies suggested that these compounds would bind to DAD2, the petunia SL receptor, with higher affinity than the first-generation compounds. However, only one of the QADs/QADDs tested in in vitro assays acted as a competitive antagonist of SL receptors, with reduced affinity and potency compared with its N-phenylanthranilic acid ‘parent’. X-ray crystal structure analysis revealed that the binding mode of the active QADD inside DAD2's cavity was not that predicted in silico, highlighting a novel inhibition mechanism for SL receptors. Despite a ∼10-fold difference in potency in vitro, the QADD and tolfenamic acid had comparable activity in planta, suggesting that the QADD compensates for lower potency with increased bioavailability. Altogether, our results establish this QADD as a novel lead compound towards the development of potent and bioavailable antagonists of SL receptors.

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