Identifying potential GluN2B subunit containing N-Methyl-D-aspartate receptor inhibitors: an integrative in silico and molecular modeling approach

Abstract

N-methyl-D-aspartate receptors (NMDARs), a class of ligand-gated ion channels, are involved in non-selective cation transport across the membrane. These are contained in glutamatergic synapse and produce excitatory effects leading to synaptic plasticity and memory function. GluN1-GluN2B, a subtype of NMDAR(s), has significant role in neurodegeneration, amyloid β (Aβ) induced synaptic dysfunction and loss. Thus, targeting and inhibiting GluN1-GluN2B may be effective in the management of neurodegenerative diseases including Alzheimer’s disease. In the present study, ligand and structure-based approaches were tried to identify the inhibitors. The pharmacophore, developed from co-crystallised ifenprodil, afforded virtual hits, which were further subjected through drug likeliness and PAINS filters to remove interfering compounds. Further comprehensive docking studies, free energy calculations and ADMET studies resulted in two virtual leads. The leads, ZINC257261614 and ZINC95977857 displayed good docking scores of ?12.90 and ?12.20?Kcal/mol and free binding energies of ?60.83 and ?61.83?Kcal/mol, respectively. The compounds were having acceptable predicted ADMET profiles and were subjected to molecular dynamic (MD) studies. The MD simulation produced stable complexes of these ligands with GluN1-GluN2B subunit having protein and ligand RMSD in acceptable limit. Abbreviations AD Alzheimer's disease

ADME Absorption distribution metabolism and excretion

ATD Amino terminal domain

BBB Blood-brain barrier

CNS Central nervous system

CREB cAMP response element binding protein

CTD Carboxy-terminal domain

Glu Glutamate

GMQE Global model quality estimation

HTVS High throughput virtual screening

HIA Human intestinal absorption

LGA Lamarckian genetic algorithm

MD Molecular dynamics

MM-GBSA Molecular mechanics, the Generalised Born model for Solvent Accessibility

NMDAR N-methyl-D-aspartate receptors

PAINS Pan assay interference compounds

RMSD Root-mean square deviation

RMSF Root-mean-square fluctuation

SMARTS SMILES arbitrary target specification

SP standard precision

XP extra precision

Communicated by Ramaswamy H. Sarma     

Vorinostat,a possible alternative to metronidazole for the treatment of amebiasis caused by Entamoeba histolytica

Abbreviations SAHA suberoylanilide hydroxamic acid

EhHDAC Histone Deacetylase from Entamoeba histolytica

Rg Radius of gyration

RMSD root-mean-square deviation

RMSF root-mean-square fluctuation

MDS molecular dynamics simulation

VMD Visual Molecular Dynamics

NAMD Nanoscale Molecular Dynamics

PBC periodic boundary conditions

PME Particle Mesh Ewald

3D three-dimensional

Cα alpha carbon

FDA Food and Drug Administration

ns nanoseconds

GPU CUDA Graphics Processing Unit Compute Unified Device Architecture

Communicated by Ramaswamy H. Sarma     

Molecular dynamics simulation studies on influenza A virus H5N1 complexed with sialic acid and fluorinated sialic acid

Abbreviations HA Hemagglutinin

MD Molecular Dynamics

MM-PBSA Molecular Mechanics Poisson–Boltzmann Surface Area

NA Neuraminidase

NAMD Nanoscale Molecular Dynamic Simulation

PMEMD Particle Mesh Ewald Molecular Dynamics

RMSD Root-Mean-Square Deviation

RMSF Root-Mean-Square Fluctuation

SIA sialic acid

VMD Visual Molecular Dynamics

Communicated by Ramaswamy H. Sarma     

Synthesis,molecular docking and ADMET study of ionic liquid as anticancer inhibitors of DNA and COX-2, TOPII enzymes

Abstract

A new ionic liquid was synthesized by the reaction of caprolactam with salicylic acid (CL-SA) and characterized by analysis of spectroscopic and DSC data. The optimized geometry and the electrostatic potential map of CL-SA were calculated with DFT method using the wb97xd/6-31++G(d,p) level of theory. Molecular docking study of the CL-SA was carried out to clarify the probable binding modes between the title compound and DNA and COX-2 and TOPII enzymes. In silico ADMET study was also performed for predicting pharmacokinetic and toxicity profile of the synthesized ionic liquid which expressed good oral drug-like behavior and non-toxic nature. It was revealed that the compound has a potential to become a lead molecule in drug discovery process.

Communicated by Ramaswamy H. Sarma     

Antimalarial drug discovery against malaria parasites through haplopine modification: An advanced computational approach

The widespread emergence of antimalarial drug resistance has created a major threat to public health. Malaria is a life-threatening infectious disease caused by Plasmodium spp., which includes Apicoplast DNA polymerase and Plasmodium falciparum cysteine protease falcipain-2. These components play a critical role in their life cycle and metabolic pathway, and are involved in the breakdown of erythrocyte hemoglobin in the host, making them promising targets for anti-malarial drug design. Our current study has been designed to explore the potential inhibitors from haplopine derivatives against these two targets using an in silico approach. A total of nine haplopine derivatives were used to perform molecular docking, and the results revealed that Ligands 03 and 05 showed strong binding affinity compared to the control compound atovaquone. Furthermore, these ligand-protein complexes underwent molecular dynamics simulations, and the results demonstrated that the complexes maintained strong stability in terms of RMSD (root mean square deviation), RMSF (root mean square fluctuation), and Rg (radius of gyration) over a 100 ns simulation period. Additionally, PCA (principal component analysis) analysis and the dynamic cross-correlation matrix showed positive outcomes for the protein-ligand complexes. Moreover, the compounds exhibited no violations of the Lipinski rule, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) predictions yielded positive results without indicating any toxicity. Finally, density functional theory (DFT) and molecular electrostatic potential calculations were conducted, revealing that the mentioned derivatives exhibited better stability and outstanding performance. Overall, this computational approach suggests that these haplopine derivatives could serve as a potential source for developing new, effective antimalarial drugs to combat malaria. However, further in vitro or in vivo studies might be conducted to determine their actual effectiveness.     

In silico based unraveling of New Delhi metallo-β-lactamase (NDM-1) inhibitors from natural compounds: a molecular docking and molecular dynamics simulation study

Abstract

The development of pathogenic microbial resistance toward antibiotics has become a global clinical concern. New Delhi metallo-β-lactmase-1 (NDM-1) and its variants have recently drawn immense attention for its biological ability to catalyze the hydrolysis of almost all of β-lactam antibiotics including the Carbapenems which are generally considered as the last-resort antibiotics. Also, the horizontal gene transfer is expediting the rapid spread of NDM-1 in bacteria. In the wake of this serious antibiotic resistance problem it becomes imperative to find inhibitors which can render the present antibiotics functional and useful. In the present study, we have used Molecular docking and Molecular Dynamics (MD) simulation approach to find out suitable inhibitors against NDM-1 from an array of different natural compounds. We have screened unique natural compounds from ZINC database and also a set of standard antibiotics and inhibitors. Based upon the highest binding affinity demonstrated by docking with NDM-1, the best binding antibiotic Meropenem and the top five natural compounds, viz., Withaferin A, Beta-Sitosterol, Aristolochic acid, Diosgenin and Guggulsterone E were selected and subjected to MD simulations study. The docked NDM-1 complex with withaferin A, beta-sitosterol and diosgenin were found to be more stable as compared to the one with meropenem throughout the MD simulation process with the relative RMSD and RMSF in acceptable range. In conclusion, these compounds can be readily tested in vitro and in vivo to fully establish and confirm their inhibition potentiality and can also serve as lead molecules for the development of future functional inhibitors.

Communicated by Ramaswamy H. Sarma     

In silico screening of anti-inflammatory compounds from Lichen by targeting cyclooxygenase-2

Abstract

Non-steroidal anti-inflammatory drugs (NSAID) targeting cyclooxygenase-2 are clinically effective. However, they lack anti-thrombotic activity resulting in incidences of adverse effects like myocardial infarction, gastrointestinal and abdominal discomfort which necessitate for discovering new drug candidates with improved therapeutic effects and tolerability. Various recent researches have suggested that many lichens offer a vast reservoir for anti-inflammatory drug candidates which are natural as well as safe for human consumption. Drug discovery is a very complex and time-consuming process; however, in silico techniques can make this process simple and economic. Hence to find out natural anti-inflammatory compounds, we have carried out the virtual screening of 412 lichen compounds by molecular docking with human Cox-2 enzyme and validated the docking score by X-Score followed by ADMET and Drug-likeness analysis. The resulting 6 top-scored compounds were subjected to Molecular dynamics simulation (MDS) to analyze the stability of docked protein-ligand complex, to assess the fluctuation and conformational changes during protein-ligand interaction. The values of RMSD, Rg, and interaction energy after 30?ns of MDS revealed the good stability of these Lichen compounds in the active site pocket of Cox-2 in compare to reference, JMS. Additionally, we have done the pharmacophore analysis which found many common pharmacophore features between Lichen compounds and well known anti-inflammatory compounds. Our result shows that these lichen compounds are potential anti-inflammatory candidates and could be further modified and evaluated to develop more effective anti-inflammatory drugs with fewer side effects for the treatment of inflammatory diseases.

Communicated by Ramaswamy H. Sarma     

Exploring the binding mechanism of saccharin and sodium saccharin to promoter of human p53 gene by theoretical and experimental methods

Abstract

In the past few decades, extensive discussions have been on the impact of artificial sweeteners on the risk of cancer. The present study aimed to evaluate the interaction of saccharin (SA) and sodium saccharin (SSA) with the promoter of the human p53 gene. The binding ability was assessed using the spectroscopic technique, molecular docking and molecular dynamics (MD) simulation methods. Free energy of binding has been calculated using Molecular Mechanics/Poisson–Boltzmann Surface Area (MM/PBSA) method. Fluorescence spectra of mentioned gene with concentration profiles of SA and SSA were obtained in a physiological condition. A gradual increase without any significant spectral shift in the fluorescence intensity of around 350?nm was evident, indicating the presence of an interaction between both compounds and gene. The docking results showed that both compounds were susceptible to bind to 5′-DG56DG57-3′ nucleotide sequence of gene. Furthermore, the MD simulation demonstrated that the binding positions for SA and SSA were 5′-A1T3T4-3′ and 5′-G44T45-3′ sequences of gene, respectively. The binding of these sweeteners to gene made significant conformational changes to the DNA structure. Hydrogen and hydrophobic interactions are the major forces in complexes stability. Through the groove binding mode, the non-interactive DNA-binding nature of SSA and SA has been demonstrated by the results of spectrofluorometric and molecular modeling. This study could provide valuable insight into the binding mechanism of SA and its salt with p53 gene promoter as macromolecule at the molecular level in atomistic details. This work can contribute to the possibility of the potential hazard of carcinogenicity of this sweetener and to design and apply new and safer artificial sweeteners. Abbreviations SA Saccharin

SSA Sodium Saccharin

Pp53g promoter of human p53 gene

MD Molecular dynamics

RMSD Root-mean-square deviation

RMSF Root-mean-square fluctuation

Rg Radius of Gyration

SASA Solvent-Accessible Surface Area

ADI Acceptable daily intake

MM/PBSA Molecular Mechanics/Poisson–Boltzmann Surface Area

Communicated by Ramaswamy H. Sarma     

Molecular Docking and Dynamic Simulation to Identify α7nAChR Binding Affinity of Flavonoids for the Treatment of Alzheimer's Disease

Background : Alpha-7-nicotinic acetylcholine receptor (α7nAChR), a ligand-gated ion channel is one of the important parts of the cholinergic pathway in the brain and has a remarkable role in Alzheimer's disease (AD). It has been documented that the modulation of α7nAChR with the help of phytoconstituent can be helpful in the treatment of AD. Method : The binding efficacy of fifty flavonoids was evaluated for human α7nAChR using molecular docking. The best two flavonoids shortlisted from docking analysis were then subjected to molecular dynamic simulations for 100 ns to analyze conformational binding stability with the target protein. Further, the druggability of the selected flavonoids was checked using in silico ADMET studies. Result : The top two flavonoids selected based on binding affinity toward the binding site of α7nAChR from molecular docking were amentoflavone (–9.1 kcal/mol) and gallocatechin (–8.8 kcal/mol). The molecular dynamics simulation revealed that amentoflavone and gallocatechin have a stable state during overall simulation time, lesser root mean deviation (RMSD) and root mean square fluctuation (RMSF), and complex of both compounds with protein is stable until 100 ns. Conclusion : The two flavonoids amentoflavone and gallocatechin are potential lead molecules that could be utilized as effective agonists of α7nAChR to combat Alzheimer's disease. Future in vitro and in vivo analyses are required to confirm their effectiveness.     

Discover potential inhibitors for PFKFB3 using 3D-QSAR,virtual screening,molecular docking and molecular dynamics simulation

Abstract

The 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) is a master regulator of glycolysis in cancer cells by synthesizing fructose-2,6-bisphosphate (F-2,6-BP), a potent allosteric activator of phosphofructokinase-1 (PFK-1), which is a rate-limiting enzyme of glycolysis. PFKFB3 is an attractive target for cancer treatment. It is valuable to discover promising inhibitors by using 3D-QSAR pharmacophore modeling, virtual screening, molecular docking and molecular dynamics simulation. Twenty molecules with known activity were used to build 3D-QSAR pharmacophore models. The best pharmacophore model was ADHR called Hypo1, which had the highest correlation value of 0.98 and the lowest RMSD of 0.82. Then, the Hypo1 was validated by cost value method, test set method and decoy set validation method. Next, the Hypo1 combined with Lipinski's rule of five and ADMET properties were employed to screen databases including Asinex and Specs, total of 1,048,159 molecules. The hits retrieved from screening were docked into protein by different procedures including HTVS, SP and XP. Finally, nine molecules were picked out as potential PFKFB3 inhibitors. The stability of PFKFB3-lead complexes was verified by 40?ns molecular dynamics simulation. The binding free energy and the energy contribution of per residue to the binding energy were calculated by MM-PBSA based on molecular dynamics simulation.     

Ligand-Guided Investigation of a Series of Formamidine-Based Thiuram Disulfides as Potential Dual-Inhibitors of COX-1and COX-2

A series of thiuram disulfides 1–6 which had been previously synthesized and characterized,^[1] were studied for their potential therapeutic properties. Target-fishing analyses through HitPick and SwissTarget prediction identified COX1 and COX2, which are essential biomolecules in cancer-related inflammations, as the possible targets for compounds 1 and 4 among all the compounds tested. These two proteins have enjoyed interest as targets for treating some neoplastic cancer types such as breast, colorectal, skin, pancreatic, haematological and head cancers. The inhibitory potency of 1 and 4 as lead anticancer drug candidates with dual-target ability against COX1 and COX2 was examined through molecular docking, molecular dynamics simulation and post-MD analyses such as binding energy calculation, RMSD, RMSF, and RoG. The two compounds had better docking scores and binding energies than the known inhibitors of COX1 and COX2. Insights from the RMSD, RMSF, and RoG suggested that both 1 and 4 showed observable influence on the structural stability of these targets throughout the simulation. The reported observations of the effects of 1 and 4 on the structures of COX1 and COX2 indicate their probable inhibitory properties against these target proteins and their potential as lead anticancer drug candidates.     

Computational Structure-Based De Novo Design of Hypothetical Inhibitors against the Anti- Inflammatory Target COX-2

Cyclooxygenase-2 (COX-2) produces prostaglandins in inflamed tissues and hence has been considered as an important target for the development of anti-inflammatory drugs since long. Administration of traditional non-steroidal anti-inflammatory drugs (NSAIDs) and other COX-2 selective inhibitors (COXIBS) for the treat of inflammation has been found to be associated with side effects, which mainly includes gastro-intestinal (GI) toxicity. The present study involves developing a virtual library of novel molecules with high druglikeliness using structure-based de novo drug designing and 2D fingerprinting approach. A library of 2657 drug like molecules was generated. 2D fingerprinting based screening of the designed library gave a unique set of compounds. Molecular docking approach was then used to identify two compounds highly specific for COX-2 isoform. Molecular dynamics simulations of protein-ligand complexes revealed that the candidate ligands were dynamically stable within the cyclooxygenase binding site of COX-2. The ligands were further analyzed for their druglikeliness, ADMET properties and synthetic accessibility using knowledge based set of rules. The results revealed that the molecules are predicted to selectively bind to COX-2 enzyme thereby potentially overcoming the limitations posed by the drugs in clinical use.     

Structural and biological study of synthesized anthraquinone series of compounds with sulfonamide feature

Abstract

1, 4 and 5, 8-Positions as well as type of functionalities on these positions at anthraquinone-9, 10-dione are proposed to be significant for anticancer activity. Therefore, keeping this into consideration, a series of 1-substituted anthraquinone-based compounds are designed, synthesized, characterized and biologically evaluated for anticancer activity. The structure of synthesized compounds is confirmed by spectroscopic analysis, i.e. 1D (¹H and ¹³C) nuclear magnetic resonance (NMR), electrospray ionization-mass spectrometry (ESI-MS) studies and Fourier transform infrared (FT-IR) tools. Synthesized 1-substituted anthraquinone compounds showed cytotoxic effect against human breast cancer cell line (MCF-7), human prostate cancer cell line (PC-3) and Hela derivative human cell line (Hep 2C) (Hela derivative) cell lines. All the compounds showed mild antibacterial property in comparison to standard antibiotic streptomycin against Gram?+?ve and –ve bacteria. They also exhibit mild antifungal activity. In vitro calf thymus (ct)-DNA binding studies of synthesized series using UV–visible absorption spectra measurement and fluorescence tools indicate partial intercalative mode of binding. Electronic properties of synthesized analogues and mitoxantrone are compared using highest occupied molecular orbital–lowest occupied molecular orbital (HOMO–LUMO) calculation. Low energy gap between HOMO and LUMO of 1-substituted anthraquinone compounds indicates the highly charged structure of the molecules in comparison to mitoxantrone, and the same is proposed to be responsible for comparable cytotoxic activities of the synthesized 1-substituted anthraquinone molecules. Docking interaction of synthesized 1-substituted anthraquinone compounds and i-motif sequence indicates intercalative mode of binding of compounds with telomeric junction.

Communicated by Ramaswamy H. Sarma     

Theoretical evaluation of inhibition performance of purine corrosion inhibitors

Inhibition mechanism of three purine compounds, adenine (A), 2-amino-6-thiol-9H-purine (B) and 2,6-dithiol-9H-purine (C), was investigated by quantum chemical calculation and molecular dynamic simulation. The molecular reactivity was studied by quantum chemical calculation, and the distribution of the highest occupied molecular orbital (HOMO), the lowest unoccupied molecular orbital (LUMO), the energy gap between HOMO and LUMO and the Fukui index were proposed to describe the active sites of molecules, and the inferred inhibition efficiency followed the order of A < B < C. Furthermore, the adsorption behaviour of these three purine molecules on a metal surface was investigated via molecular dynamics simulation. The analysis of adsorption configuration indicated that these three purine molecules adsorbed parallely onto the metal surface, and the inferred inhibition efficiency from interaction energy also followed the order of A < B < C. These inferred inhibition efficiency from theoretical calculation was in good accordance with experimental results. This accordance indicated that our proposed theoretical method might be a feasible approach to assess the inhibition performance of inhibitors. Moreover, our research was helpful to filter the aimed inhibitor and design of the new inhibitor.     

Evaluation of binding and antagonism/downregulation of brilanestrant molecule in estrogen receptor-α via quantum mechanics/molecular mechanics,molecular dynamics and binding free energy calculations

Abstract

The resistance to the endocrine therapy of breast cancer leads to the emergence of new class of drugs that downregulates the estrogen receptor action known as selective estrogen receptor downregulators (SERDs). The first approved SERD is fluvestrant; after this, there are several downregulators evolved and are in clinical trials, in which the brilanestrant (BRI) molecule shows nM range of binding affinity and efficacy. In the present study, to understand the binding nature of BRI molecule in the active site of ERα, the molecular docking analysis has been performed. Further, the QM/MM calculations were performed for the BRI–ERα complex to analyze the charge density distribution of intermolecular interactions. The molecular dynamics (MD) simulation was employed to understand the stability and binding mechanism of BRI molecule through root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF) and binding free energy calculations. From the MD simulation trajectory analysis, the alterations of Helix12 conformation and the key residue (Lys529), which is responsible for the ERα downregulation, have been identified. Further, the interaction between the H3 and H12 regions was identified for the antagonism of BRI molecule. The current study led us to understand the binding mechanism, antagonism and downregulation of BRI molecule, and this knowledge is essential to design novel SERDs for the treatment of endocrine-resistant positive breast cancer.

Communicated by Ramaswamy H. Sarma     

Developing Hispolon-based novel anticancer therapeutics against human (NF-κβ) using in silico approach of modelling,docking and protein dynamics

Abstract

Hispolon is a polyphenolic compound derived from black hoof mushroom (Phellinus linteus) or shaggy bracket mushroom (Inonotus hispidus) which induces the inhibition of cancer-promoting nuclear factor-kappa beta (NF-κβ) complex. To develop more potent lead molecules with enhanced anticancer efficiency, the mechanism of hispolon-mediated nuclear factor-κβ inhibition has been investigated by molecular modelling and docking. Ten derivatives of hispolon (DRG1-10) have been developed by pharmacophore-based design with a view to enhance the anticancer efficacy. Hispolon and its derivatives were further screened for different pharmacological parameters like binding free energy, drug likeliness, absorption–digestion–metabolism–excretion (ADME), permeability, mutagenicity, toxicity and inhibitory concentration 50 (IC50) to find a potent lead molecule. Based on pharmacological validation, comparative molecular dynamics (MD) simulations have been performed for three lead molecules: Hispolon, DRG2 and DRG7 complexed with human NF-κβ up to 50?ns. By analysing different factors like root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA) and principal component analysis (PCA), Gibb’s free energy plots DRG2 have more binding efficiency compared to hispolon and DRG7. In RMSD plot, hispolon-bound NF-κβ has the most deviation within a range between 0.125 and 0.45?nm, and DRG2-bound complex showed the range between 0.125 and 0.25?nm. The residues of NF-κβ responsible for hydrophobic interactions with ligand, e.g. Met469, Leu522 and Cys533, have the lowest fluctuation values in DRG2-bound complex. The average Rg fluctuation for DRG2-bound NF-κβ has been recorded under 2.025?nm for most of the simulation time which is much less compared to hispolon and DRG7. Gibb’s free energy plots also define the highest stability of DRG2-bound NF-κβ.

Communicated by Ramaswamy H. Sarma     

Virtual identification of novel PPARα/γ dual agonists by 3D-QSAR,molecule docking and molecular dynamics studies

Abstract

Peroxisome proliferator-activated receptors (PPARs) are considered important targets for the treatment of Type 2 diabetes (T2DM). To accelerate the discovery of PPAR α/γ dual agonists, the comparative molecular field analysis (CoMFA) were performed for PPARα and PPARγ, respectively. Based on the molecular alignment, highly predictive CoMFA model for PPARα was obtained with a cross-validated q² value of 0.741 and a conventional r² of 0.975 in the non-cross-validated partial least-squares (PLS) analysis, while the CoMFA model for PPARγ with a better predictive ability was shown with q² and r² values of 0.557 and 0.996, respectively. Contour maps derived from the 3D-QSAR models provided information on main factors towards the activity. Then, we carried out structural optimization and designed several new compounds to improve the predicted biological activity. To investigate the binding modes of the predicted compounds in the active site of PPARα/γ, a molecular docking simulation was carried out. Molecular dynamic (MD) simulations indicated that the predicted ligands were stable in the active site of PPARα/γ. Therefore, combination of the CoMFA and structure-based drug design results could be used for further structural alteration and synthesis and development of novel and potent dual agonists. Abbreviations DM diabetes mellitus

T2DM type 2 diabetes

PPARs peroxisome proliferator-activated receptors

LBDD ligand based drug design

3D-QSAR three-dimensional quantitative structure activity relationship

CoMFA comparative molecular field analysis

PLS partial least square

LOO leave-one-out

q² cross-validated correlation coefficient

ONC optimal number of principal components

r² non-cross-validated correlation coefficient

SEE standard error of estimate

F the Fischer ratio

r²_pred predictive correlation coefficient

DBD DNA binding domain

MD molecular dynamics

RMSD root-mean-square deviation

RMSF root mean square fluctuations

Communicated by Ramaswamy H. Sarma