scholarly journals Computational guided identification of potential leads from Acacia pennata (L.) Willd. as inhibitors for cellular entry and viral replication of SARS-CoV-2

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
James H. Zothantluanga ◽  
Neelutpal Gogoi ◽  
Anshul Shakya ◽  
Dipak Chetia ◽  
H. Lalthanzara
Keyword(s):  
Oxygen Atom ◽  
Viral Replication ◽  
Docking Simulation ◽  
Md Simulations ◽  
Active Site Residues ◽  
Stable Conformation ◽  
Synthetic Accessibility ◽  
In Silico Studies ◽  
Cellular Entry ◽  
Potential Inhibitors

Abstract Background Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started in 2019 and is still an on-going pandemic. SARS-CoV-2 uses a human protease called furin to aid in cellular entry and its main protease (Mpro) to achieve viral replication. By targeting these proteins, scientists are trying to identify phytoconstituents of medicinal plants as potential therapeutics for COVID-19. Therefore, our study was aimed to identify promising leads as potential inhibitors of SARS-CoV-2 Mpro and furin using the phytocompounds reported to be isolated from Acacia pennata (L.) Willd. Results A total of 29 phytocompounds were reported to be isolated from A. pennata. Molecular docking simulation studies revealed 9 phytocompounds as having the top 5 binding affinities towards SARS-CoV-2 Mpro and furin. Among these phytocompounds, quercetin-3-O-α-L-rhamnopyranoside (C_18), kaempferol 3-O-α-L-rhamnopyranosyl-(1 → 4)-β-D-glucopyranoside (C_4), and isovitexin (C_5) have the highest drug score. However, C_18 and C_4 were not selected for further studies due to bioavailability issues and low synthetic accessibility. Based on binding affinity, molecular properties, drug-likeness, toxicity parameters, ligand interactions, bioavailability, synthetic accessibility, structure–activity relationship, and comparative analysis of our experimental findings with other studies, C_5 was identified as the most promising phytocompound. C_5 interacted with the active site residues of SARS-CoV-2 Mpro (GLU166, ARG188, GLN189) and furin (ASN295, ARG298, HIS364, THR365). Many phytocompounds that interacted with these amino acid residues were reported by other studies as potential inhibitors of SARS-CoV-2 Mpro and furin. The oxygen atom at position 18, the –OH group at position 19, and the 6-C-glucoside were identified as the pharmacophores in isovitexin (also known as apigenin-6-C-glucoside). Other in-silico studies reported apigenin as a potential inhibitor of SARS-CoV-2 Mpro and apigenin-o-7-glucuronide was reported to show stable conformation during MD simulations with SARS-CoV-2 Mpro. Conclusion The present study found isovitexin as the most promising phytocompound to potentially inhibit the cellular entry and viral replication of SARS-CoV-2. We also conclude that compounds having oxygen atom at position 18 (C-ring), –OH group at position 19 (A-ring), and 6-C-glucoside attached to the A-ring at position 3 on a C6–C3–C6 flavonoid scaffold could offer the best alternative to develop new leads against SARS-CoV-2.

In Silico study of Rosmarinic Acid Derivatives as Novel Insulin Fibril Inhibitors

2021 ◽  
Vol 20 (06) ◽  
pp. 641-654
Author(s):  
Kaushik Sarkar ◽  
Rajesh Kumar Das
Keyword(s):  
Self Assembly ◽  
In Silico ◽  
Rosmarinic Acid ◽  
Amyloid Fibrils ◽  
Md Simulations ◽  
Amyloid Formation ◽  
Drug Candidates ◽  
In Silico Studies ◽  
The Stability ◽  
Potential Inhibitors

The self-assembly of human insulin (HI) plays a crucial role in regulating amyloid fibrils. Therefore, it is a significant problem for the medical management of diabetes therapy and these findings have led us to investigate the amyloid formation and its inhibition. Few potential inhibitors have been identified to inhibit amyloid fibrils. Rosmarinic acid (RA) is one of the things that inhibits amyloid formation completely by increasing the resistivity of the amyloidogenic insulin (dimer) protein to thermal unfolding. Here, we choose different tested derivative compounds for designing amyloid inhibitors by substituting various functional groups of RA. These derivative compounds were subjected to in silico studies to determine the best drug candidates. In comparison to RA, 14 molecules have higher binding affinity and interactions with the target receptor. After frontier molecular orbitals study, ADME and toxicity analysis, the eight best compounds may act as the best inhibitors. The stability of the docked complexes was visualized by molecular dynamics (MD) simulations. This finding opens a new proposal to explore future studies with these best compounds to increase the thermal stability of the insulin dimers.

scholarly journals A Possible Mechanism of Graphene Oxide to Enhance Thermostability of D-Psicose 3-Epimerase Revealed by Molecular Dynamics Simulations

2021 ◽  
Vol 22 (19) ◽  
pp. 10813
Author(s):  
Congcong Li ◽  
Zhongkui Lu ◽  
Min Wang ◽  
Siao Chen ◽  
Lu Han ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Thermal Stability ◽  
Graphene Oxide ◽  
Md Simulations ◽  
Strong Interactions ◽  
Limiting Factor ◽  
Active Site Residues ◽  
Detailed Mechanism ◽  
Dynamics Simulations ◽  
Thermal Stability Of

Thermal stability is a limiting factor for effective application of D-psicose 3-epimerase (DPEase) enzyme. Recently, it was reported that the thermal stability of DPEase was improved by immobilizing enzymes on graphene oxide (GO) nanoparticles. However, the detailed mechanism is not known. In this study, we investigated interaction details between GO and DPEase by performing molecular dynamics (MD) simulations. The results indicated that the domain (K248 to D268) of DPEase was an important anchor for immobilizing DPEase on GO surface. Moreover, the strong interactions between DPEase and GO can prevent loop α1′-α1 and β4-α4 of DPEase from the drastic fluctuation. Since these two loops contained active site residues, the geometry of the active pocket of the enzyme remained stable at high temperature after the DPEase was immobilized by GO, which facilitated efficient catalytic activity of the enzyme. Our research provided a detailed mechanism for the interaction between GO and DPEase at the nano–biology interface.

scholarly journals Potential Smoothened Inhibitor from Traditional Chinese Medicine against the Disease of Diabetes, Obesity, and Cancer

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Kuan-Chung Chen ◽  
Mao-Feng Sun ◽  
Hsin-Yi Chen ◽  
Cheng-Chun Lee ◽  
Calvin Yu-Chian Chen
Keyword(s):  
Drug Development ◽  
Hedgehog Signaling ◽  
Docking Simulation ◽  
Md Simulations ◽  
Positive Control ◽  
Lead Compounds ◽  
Oncology Clinical Trials ◽  
Body Patterning ◽  
The Stability ◽  
Smo Inhibitor

Nowadays, obesity becomes a serious global problem, which can induce a series of diseases such as type 2 diabetes mellitus, cancer, cardiovascular disease, metabolic syndrome, and stoke. For the mechanisms of diseases, the hedgehog signaling pathway plays an important role in body patterning during embryogenesis. For this reason, smoothened homologue (Smo) protein had been indicated as the drug target. In addition, the small-molecule Smo inhibitor had also been used in oncology clinical trials. To improve drug development of TCM compounds, we aim to investigate the potent lead compounds as Smo inhibitor from the TCM compounds in TCM Database@Taiwan. The top three TCM compounds, precatorine, labiatic acid, and 2,2′-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid), have displayed higher potent binding affinities than the positive control, LY2940680, in the docking simulation. After MD simulations, which can optimize the result of docking simulation and validate the stability of H-bonds between each ligand and Smo protein under dynamic conditions, top three TCM compounds maintain most of interactions with Smo protein, which keep the ligand binding stable in the binding domain. Hence, we propose precatorine, labiatic acid, and 2,2′-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid) as potential lead compounds for further study in drug development process with the Smo protein.

Molecular docking and molecular dynamics simulations of fumarate hydratase and its mutant H235N complexed with pyromellitic acid and citrate

2017 ◽  
Vol 15 (06) ◽  
pp. 1750026 ◽  
Author(s):  
S. Subasri ◽  
Santosh Kumar Chaudhary ◽  
K. Sekar ◽  
Manish Kesherwani ◽  
D. Velmurugan
Keyword(s):  
Molecular Dynamics ◽  
Active Site ◽  
Model Building ◽  
Hydrophobic Interactions ◽  
Conformational Stability ◽  
Fumarate Hydratase ◽  
Md Simulations ◽  
Major Effect ◽  
Active Site Residues ◽  
Pyromellitic Acid

Fumarase catalyzes the reversible, stereospecific hydration/dehydration of fumarate to L-malate during the Kreb’s cycle. In the crystal structure of the tetrameric fumarase, it was found that some of the active site residues S145, T147, N188 G364 and H235 had water-mediated hydrogen bonding interactions with pyromellitic acid and citrate which help to the protonation state for the conversion of fumarate to malate. When His 235 is mutated with Asn (H235N), water-mediated interactions were lost due to the shifting of active site water molecule by 0.7 Å away. Molecular dynamics (MD) simulations were also carried out by NAMD and analyzed using Assisted Model Building with Energy Refinement (AMBER) program to better understand the conformational stability and other aspects during the binding of pyromellitic acid and citrate with native and mutant FH. The role of hydrogen bonds and hydrophobic interactions was also analyzed. The present study confirms that the H235N mutation has a major effect on the catalytic activity of fumarase which is evident from the biochemical studies.

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

Processes ◽  
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.

scholarly journals In silico screening of W. salutaris bioactive constituents reveal betulinic acid, ursolic acid acetate and eucosterol as potential M. tuberculosis antagonists targeting FabF

2021 ◽  
Author(s):  
Nokukhanya Gumede ◽  
Kgothatso E. Machaba ◽  
Umar Ndagi ◽  
Hezekiel M. Kumalo ◽  
Ndumiso N. Mhlongo
Keyword(s):  
Ursolic Acid ◽  
Betulinic Acid ◽  
In Silico ◽  
Fatty Acid Biosynthesis ◽  
Binding Energies ◽  
Active Site Residues ◽  
Bioactive Constituents ◽  
Inhibitory Potential ◽  
Dynamics Simulations ◽  
Potential Inhibitors

Abstract Tuberculosis (TB) remains a long-standing burdening disease to control worldwide. The lengthy current TB treatment, which boasts with unbearable adverse effects, and frequent emergence of drug resistant strains of M. tuberculosis lays an increasing burden. This behests urgent discovery and development of alternative novel medicine to alleviate TB. In this report, in silico methods were applied to examine the propensity of W. salutaris active compounds as potential inhibitors of M. tuberculosis fatty acid biosynthesis protein (FabF). Thirteen compounds were virtually screened against FabF and subjected to molecular dynamics simulations and post-dynamics analyses to examine their inhibitory potential. Betulinic acid, ursolic acid and ursolic acid acetate had the best binding energies and hence the best inhibitory potential against FabF and desirable cytotoxicity profile. These compounds bind and interact with FabF active site residues to exert their inhibitory potential. Findings in this preliminary report warrant further experimental validation towards the development of these compounds as potential drugs targeting FabF in the treatment of tuberculosis.

scholarly journals Repurposing FDA Drug Compounds against Breast Cancer by Targeting EGFR/HER2

2021 ◽  
Vol 14 (8) ◽  
pp. 791
Author(s):  
Irving Balbuena-Rebolledo ◽  
Itzia Irene Padilla-Martínez ◽  
Martha Cecilia Rosales-Hernández ◽  
Martiniano Bello
Keyword(s):  
Breast Cancer ◽  
Growth Factor Receptor ◽  
Md Simulations ◽  
New Drugs ◽  
Breast Cancer Cell Lines ◽  
Vitro Assay ◽  
Growth Inhibitory ◽  
Growth Inhibitory Activity ◽  
Potential Inhibitors

Repurposing studies have identified several FDA-approved compounds as potential inhibitors of the intracellular domain of epidermal growth factor receptor 1 (EGFR) and human epidermal receptor 2 (HER2). EGFR and HER2 represent important targets for the design of new drugs against different types of cancer, and recently, differences in affinity depending on active or inactive states of EGFR or HER2 have been identified. In this study, we first identified FDA-approved compounds with similar structures in the DrugBank to lapatinib and gefitinib, two known inhibitors of EGFR and HER2. The selected compounds were submitted to docking and molecular dynamics MD simulations with the molecular mechanics generalized Born surface area approach to discover the conformational and thermodynamic basis for the recognition of these compounds on EGFR and HER2. These theoretical studies showed that compounds reached the ligand-binding site of EGFR and HER2, and some of the repurposed compounds did not interact with residues involved in drug resistance. An in vitro assay performed on two different breast cancer cell lines, MCF-7, and MDA-MB-23, showed growth inhibitory activity for these repurposed compounds on tumorigenic cells at micromolar concentrations. These repurposed compounds open up the possibility of generating new anticancer treatments by targeting HER2 and EGFR.

scholarly journals Extended insight into the preponderance of LRRs - a docking & simulation study with members of the TLR1 subfamily

2019 ◽  
Author(s):  
Debayan Dey ◽  
Dipanjana Dhar ◽  
Sucharita Das ◽  
Aditi Maulik ◽  
Soumalee Basu
Keyword(s):  
Phylogenetic Analyses ◽  
Interleukin 1 ◽  
Docking Simulation ◽  
Md Simulations ◽  
Structural Motif ◽  
Cellular Processes ◽  
Binding Function ◽  
C Terminus ◽  
Evolutionarily Conserved ◽  
Leucine Rich Repeats

AbstractThe widespread structural motif of Leucine-rich repeats (LRR) constitute the extracellular part of the Toll-like receptor (TLR) family preceded by an intracellular Toll/interleukin-1 receptor (TIR) domain at the C-terminus. The benefit of using LRRs in these pattern recognition receptors (PRR) that are responsible for early detection of pathogens to elicit inflammatory/innate immune response still remains elusive. Phylogenetic analyses (Maximum Likelihood and Bayesian Inference) of nine TLR (TLR 1-9) genes from 36 mammals reconfirmed the existence of two distinct clades, one (TLR1/2/6) for recognizing bacterial cell wall derivatives and another (TLR7/8/9) for various nucleic acids. TLR3, TLR4 and TLR5 showed independent line of evolution. The distinction of the TLR1 subfamily to form heterodimers within its members and the existence of the paralogs TLR1 and TLR6 therein, was appealing enough to carry out further studies with the extracellular recognition domain. Dimerizing and ligand binding residues from the crystal structures of TLR1 and TLR6 were interchanged to generate chimeric proteins. The dimer forming ability of these variants with their common partner, TLR2, were checked before running MD simulations. The chimeras were compared with wild type dimers to find no significant alterations in the overall structure. Finally, interchanged ligands were docked to the variants to ratify reversal of the binding function. Intriguingly, sequence change in substantial numbers, 16 in TLR1 and 18 in TLR6, preserves the native scaffold offered by LRRs. This exercise thus depicts how the LRR motif has been advantageous to be selected as an evolutionarily conserved motif for essential cellular processes.

scholarly journals Computational Studies to Identify Potential Main Protease Inhibitors for SARS-CoV-2

2020 ◽  
Author(s):  
M. Elizabeth Sobhia ◽  
Ketan Ghosh ◽  
Srikanth Sivangula ◽  
Harmanpreet Singh ◽  
Siva Kumar
Keyword(s):  
In Silico ◽  
Experimental Studies ◽  
Binding Pocket ◽  
Vital Role ◽  
Active Site Residues ◽  
X Ray Diffraction ◽  
Main Protease ◽  
Docking Protocol ◽  
In Silico Studies

The Coronavirus pandemic has put the entire humanity in total shock and has forced the world to go under total lockdown. It is time for the entire scientific community across the globe to find a solution for this deadly and unseen enemy. In silico studies play a vital role in situations like this, as experimental studies are not feasible by all researchers particularly with relevance to BSL4 procedures. In this study, using the high resolution crystal structure of SARS-CoV-2 main protease (PDB: 5R82), we have identified molecules which can potentially inhibit the main protease (Mpro). We used a three-tier docking protocol making use of three different databases. We analysed the residues which are lying near the ligand binding pocket of the main protease structure and it shows a wide cavity, which can accommodate chemically diverse ligands, occupying different sub-pockets. Using the small fragment bound in the 5R82, we have identified several larger molecules whose functional groups make interactions with the active site residues covering. This study also presumably steers the structure determination of many ligand-main protease complexes using x- ray diffraction methods. These molecules can be used as ‘in silico leads’ and further be explored in the development of SARS-CoV-2 drugs.

scholarly journals Resistance from Afar: Distal Mutation V36M Allosterically Modulates the Active Site to Accentuate Drug Resistance in HCV NS3/4A Protease

2018 ◽  
Author(s):  
Ayşegül Özen ◽  
Kuan-Hung Lin ◽  
Keith P Romano ◽  
Davide Tavella ◽  
Alicia Newton ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Conformational Changes ◽  
Active Site ◽  
Md Simulations ◽  
Drug Susceptibility ◽  
Active Site Residues ◽  
Allosteric Coupling ◽  
Direct Acting ◽  
Distal Mutation ◽  
Active Site Mutations

AbstractHepatitis C virus rapidly evolves, conferring resistance to direct acting antivirals. While resistance via active site mutations in the viral NS3/4A protease has been well characterized, the mechanism for resistance of non-active site mutations is unclear. R155K and V36M often co-evolve and while R155K alters the electrostatic network at the binding site, V36M is more than 13 Å away. In this study the mechanism by which V36M confers resistance, in the context of R155K, is elucidated with drug susceptibility assays, crystal structures, and molecular dynamics (MD) simulations for three protease inhibitors: telaprevir, boceprevir and danoprevir. The R155K and R155K/V36M crystal structures differ in the α-2 helix and E2 strand near the active site, with alternative conformations at M36 and side chains of active site residues D168 and R123, revealing an allosteric coupling, which persists dynamically in MD simulations, between the distal mutation and the active site. This allosteric modulation validates the network hypothesis and elucidates how distal mutations confer resistance through propagation of conformational changes to the active site.

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