Unveiling molecular insights: in silico exploration of TLR4 antagonist for management of dry eye syndrome.

BACKGROUND: Dry eye disease is the most commonplace multifractional ocular complication, which has already affected millions of people in the world. It is identified by the excessive buildup of reactive oxygen species, leading to substantial corneal epithelial cell demise and ocular surface inflammation attributed to TLR4. In this study, we aimed to identify potential compounds to treat of dry eye syndrome by exploring in silico methods. METHODS: In this research, molecular docking and dynamics simulation tests were used to examine the effects of selected compounds on TLR4 receptor. Compounds were extracted from different databases and were prepared and docked against TLR4 receptor via Autodock Vina. Celastrol, lumacaftor and nilotinib were selected for further molecular dynamics studies for a deeper understanding of molecular systems consisting of protein and ligands by using the Desmond module of the Schrodinger Suite. RESULTS: The docking results revealed that the compounds are having binding affinity in the range of -5.1 to -8.78 based on the binding affinity and three-dimensional interactions celastrol, lumacaftor and nilotinib were further studied for their activity by molecular dynamics. Among the three compounds, celastrol was the most stable based on molecular dynamics trajectory analysis from 100 ns in the catalytic pockets of 2Z63.pdb.pdb. Root mean square deviation of celastrol/2Z63 was in the range of 1.8-4.8 Å. CONCLUSION: In particular, Glu376 of TLR4 receptor is crucial for the identification and binding of lipopolysaccharides (LPS), which are part of Gram-negative bacteria's outer membrane. In our investigation, celastrol binds to Glu376, suggesting that celastrol may prevent the dry eye syndrome by inhibiting LPS's binding to TLR4.

A Review on Neuroinflammatory Pathway Mediating Through Ang-II/AT1 Receptors and a Novel Approach for the Treatment of Cerebral Ischemia in Combination with ARB's and Ceftriaxone.

Background: Ischemic stroke is one of the prevalent neurodegenerative disorders; it is generally characterized by sudden abruption of blood flow due to thromboembolism and vascular abnormalities, eventually impairing the supply of oxygen and nutrients to the brain for its metabolic needs. Oxygen-glucose deprived conditions provoke the release of excessive glutamate, which causes excitotoxicity. Summary: Recent studies suggest that circulatory angiotensin-II (Ang-II) has an imperative role in initiating detrimental events through binding central angiotensin 1 (AT1) receptors. Insufficient energy metabolites and essential ions often lead to oxidative stress during ischemic reperfusion, which leads to the release of proinflammatory mediators such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and cytokines like interleukin-18 (IL-18) and interleukin- 1beta (IL-1ß). The transmembrane glutamate transporters, excitatory amino acid transporter-2 (EAAT-2), which express in astroglial cells, have a crucial role in the clearance of glutamate from its releasing site and convert glutamate into glutamine in normal circumstances of brain physiology. Key Message: During cerebral ischemia, an impairment or dysfunction of EAAT-2 attributes the risk of delayed neuronal cell death. Earlier studies evidencing that angiotensin receptor blockers (ARB) attenuate neuroinflammation by inhibiting the Ang-II/AT1 receptor-mediated inflammatory pathway and that ceftriaxone ameliorates the excitotoxicity-induced neuronal deterioration by enhancing the transcription and expression of EAAT-2 via the nuclear transcriptional factor kappa-B (NF-kB) signaling pathway. The present review will briefly discuss the mechanisms involved in Ang-II/AT1-mediated neuroinflammation, ceftriaxone-induced EAAT-2 expression, and the repurposing hypothesis of the novel combination of ARBs and ceftriaxone for the treatment of cerebral ischemia.

The identification of c-Abl inhibitors as potential agents for Parkinson's disease: a preliminary in silico approach.

Parkinson's disease (PD) is the most common movement disorder worldwide. PD is primarily associated with the mutation, overexpression, and phosphorylation of α-synuclein. At the molecular level, the upstream protein c-Abl, a tyrosine kinase, has been shown to regulate α-synuclein activation and expression patterns. This study aimed to identify potential c-Abl inhibitors through in silico approaches. Molecular docking was performed using PyRx software, followed by Prime MM-GBSA studies. BBB permeability and toxicity were predicted using CBligand and ProTox-II, respectively. ADME was assessed using QikProp. Molecular dynamics were carried out using Desmond (Academic version). DFT calculations were performed using the Gaussian 16 suite program. The binding scores of the top hits, norimatinib, DB07326, and entinostat were - 11.8 kcal/mol, - 11.8 kcal/mol, and - 10.8 kcal/mol, respectively. These hits displayed drug-likeness with acceptable ADME properties, except for the standard, nilotinib, which violated Lipinski's rule of five. Similarly, the molecular dynamics showed that the top hits remained stable during the 100 ns simulation. DFT results indicate DB04739 as a potent reactive hit. While based on toxicity prediction, entinostat may be a potential candidate for preclinical and clinical testing in PD. Further studies are warranted to confirm the activity and efficacy of these ligands for PD.

Molecular insights in repurposing selective COX-2 inhibitor celecoxib against matrix metalloproteinases in potentiating delayed wound healing: a molecular docking and MMPB/SA based analysis of molecular dynamic simulations.

Matrix metalloproteinases (MMPs) are proteolytic enzymes that play a role in healing, including reducing inflammation, promoting fibroblast and keratinocyte migration, and modifying scar tissue. Due to their pleiotropic functions in the wound-healing process in diabetic wounds, MMPs constitute a significant cause of delayed wound closure. COX-2 inhibitors are proven to inhibit inflammation. The present study aims to repurpose celecoxib against MMP-2, MMP-8 and MMP-9 through in silico approaches, such as molecular docking, molecular dynamics, and MMPB/SA analysis. We considered five selective COX-2 inhibitors (celecoxib, etoricoxib, lumiracoxib, rofecoxib and valdecoxib) for our study against MMPs. Based on molecular docking study and hydrogen bonding pattern, celecoxib in complex with three MMPs was further analyzed using 1 µs (1000 ns) molecular dynamics simulation and MMPB/SA techniques. These studies identified that celecoxib exhibited significant binding affinity -8.8, -7.9 and -8.3 kcal/mol, respectively, against MMP-2, MMP-8 and MMP-9. Celecoxib formed hydrogen bonding and hydrophobic (π-π) interactions with crucial substrate pocket amino acids, which may be accountable for their inhibitory nature. The MMPB/SA studies showed that electrostatic and van der Waal energy terms favoured the total free binding energy component, while polar solvation terms were highly disfavored. The in silico analysis of the secondary structures showed that the celecoxib binding conformation maintains relatively stable along the simulation trajectories. These findings provide some key clues regarding the accommodation of celecoxib in the substrate binding S1' pocket and also provide structural insights and challenges in repurposing drugs as new MMP inhibitors with anti-inflammatory and anti-inflammatory wound-healing properties.Communicated by Ramaswamy H. Sarma.

Rational design of thiazolidine-4-one-gallic acid hybrid derivatives as selective partial PPARγ modulators: an in-silico approach for type 2 diabetes treatment.

Type 2 diabetes mellitus is a bipolar metabolic disorder characterized by abnormalities in insulin production from ß-cells and insulin resistance. Thiazolidinediones are potent anti-diabetic agents that act through the modulation of the peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor. However, their full agonistic activity leads to severe side effects by stabilizing Helix12 through strong hydrogen bonding with the TYR473 residue. Partial and selective PPARγ modulators (GW0072, GQ16, VSP-51, MRL-20, MBX-213, INT131) have demonstrated superior results compared to full agonists without causing adverse effects, as reported in existing data. To address this uncertainty and advance therapeutic options, we identified and designed a novel class of compounds (A1-A23) based on a hybrid structure combining phenolic and Thiazolidine-4-one's moieties. Our rational drug design strategy incorporated structural-activity relationship principle, and validated the docking studies through calculated the root mean square deviation. Additionally, we conducted molecular docking, binding energy, molecular dynamics simulations, and post-molecular dynamics calculations to evaluate the dynamics behavior between the ligands and protein. The selected ligands demonstrated highly favorable docking scores and binding energies, comparable to the co-crystal (rosiglitazone) such as A12 (-13.9 kcal/mol and -86.2 kcal/mol), A1 (-11.1 kcal/mol and -79.5 kcal/mol), A13 (-11.3 kcal/mol and -91.4 kcal/mol), and the co-crystal itself (-9.8 kcal/mol and -76 kcal/mol), respectively. Finally, the MD revealed that, the selected ligands were equally contributed for stabilization of Helix12 and ß-sheets. It was concluded, the designed ligands (A12, A1, and A13) exhibited weaker hydrogen-bond interactions with specific residue TYR473 which partially modulated the PPARγ protein.Communicated by Ramaswamy H. Sarma.

Drug target of natural products and COVID-19: how far has science progressed?

The new coronavirus [severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)] that caused a viral disease with a high risk of mortality (coronavirus disease 2019) was found toward the end of 2019. This was a significant acute respiratory syndrome. In a brief period, this virus spread throughout the entire planet, causing tremendous loss of life and economic damage. The process of developing new treatments takes time, and there are presently no recognized specific treatments to treat this infection. The most promising participants, who subsequently developed into prospective leads, were dropped from the clinical research in their latter phases. Medication that has previously acquired permission may only be repurposed for use for various medical reasons following a thorough investigation for safety and effectiveness. Because there are now no effective treatments available, natural products are being used haphazardly as antiviral medications and immunity boosters. The fundamental statement that most natural compounds have powerful antiviral action does not apply to SARS-CoV-2. Middle East respiratory syndrome coronavirus and severe acute respiratory syndrome coronavirus infections are inhibited by natural treatments. According to an in silico study, the virus' nonstructural proteins, including PLpro, Mpro, and RdRp, as well as structural proteins like the spike (S) protein, have been shown to have a strong affinity for several natural products and to be inhibited by them. The virus also suggests that it is a valid candidate for therapeutic research since it utilizes the intracellular angiotensin-converting enzyme 2 receptor of the host cell. In this study, interesting targets for SARS-CoV-2 medication development are explored, as well as the antiviral properties of some well-known natural compounds.

Virtual high throughput screening of natural peptides against ErbB1 and ErbB2 to identify potential inhibitors for cancer chemotherapy.

Human epidermal growth factor receptors (EGFR), namely ErbB1/HER1, ErbB2/HER2/neu, ErbB3/HER3, and ErbB4/HER4, the trans-membrane family of tyrosine kinase receptors, are overexpressed in many types of cancers. These receptors play an important role in cell proliferation, differentiation, invasion, metastasis and angiogenesis including unregulated activation of cancer cells. Overexpression of ErbB1 and ErbB2 that occurs in several types of cancers is associated with poor prognosis leading to resistance to ErbB1-directed therapies. In this connection, promising strategy to overcome the disadvantages of the existing chemotherapeutic drugs is the use of short peptides as anticancer agents. In the present study, we have performed virtual high throughput screening of natural peptides against ErbB1 and ErbB2 to identify potential dual inhibitors and identified five inhibitors based on their binding affinities, ADMET analysis, MD simulation studies and calculation of free energy of binding. These natural peptides could be further exploited for developing drugs for treating cancer.Communicated by Ramaswamy H. Sarma.

In-silico docking and molecular dynamic introspective study of multiple targets of AChE with Rivastigmine and NMDA receptors with Riluzole for Alzheimer's disease.

The present study was initiated with PDB selection and validation where 11 acetylcholinesterase (AChE) and 4 N-methyl-D-aspartate receptor (NMDAR) proteins were considered for docking with Rivastigmine and Riluzole respectively. Out of the 15 proteins, selected significant binding was observed for AChE, with 5FPQ, and NMDA receptors with 5I2K. Molecular docking studies of 5FPQ/Rivastigmine complex displayed a binding score of -8.6 kcal/mol, and the predicted inhibitory concentration (Ki) was found to be 31 nM, whereas the 5I2K/Riluzole complex showed a binding score of -9.6 kcal/mol, with an inhibitory concentration (Ki) of 21 nM. Riluzole in complex with 5I2K formed predominant π-π stacking interactions with Tyr144, pi-alkyl interaction with Pro129, and conventional hydrogen bond with Phe130. In contrast, Rivastigmine in a complex with 5FPQ formed a hydrogen bond with Gln413 and pi-alkyl with Pro537. Molecular dynamics simulation study of both complexes 5FPQ/Rivastigmine and 5I2K/Riluzole exhibited stable RMSD, RMSF, Rg, and significant numbers of hydrogen bonds. From free energy landscape (FEL) analysis both complexes were observed to achieve global minima. Overall, molecular docking and MD simulation with subsequent binding free energies studies (MM-PBSA) elucidate the binding conformations and stability of these reprogrammed drugs in the AChE and NMDAR targets. From these in-silico predictions, it can be suggested that both Rivastigmine and Riluzole combination may provide better insights as a starting point combination therapy for the treatment of Alzheimer's disease.Communicated by Ramaswamy H. Sarma.

Ceftriaxone induces glial EAAT-2 promotor region via NF-kB conformational changes: An interaction analysis using HADDOCK.

Excitotoxicity, depletion of energy metabolites, and ionic imbalance are the major factors involved in neurodegeneration mediated through excitatory amino acid transporter-2 (EAAT-2) dysfunction in ischemic insult. Recent studies have revealed that ceftriaxone expresses EAAT-2 via nuclear transcription factor kappa-B (NF-kB) signaling pathway, stimulation of EAAT-2 expression in the ischemic, and excitotoxic conditions that could provide potential benefits to control neurodegeneration. In this study, we have predicted the in silico model for interaction between NF-kB and EAAT-2 promoter region to rule out the conformational changes for the expression of EAAT-2 protein. Using homology-built model of NF-kB, we identified ceftriaxone-induced conformational changes in gene locus -272 of DNA where NF-kB binding with EAAT-2 promoter region through protein-DNA docking calculation. The interaction profile and conformational dynamics occurred between ceftriaxone predocked and postdocked conformations of NF-kB with DNA employing HADDOCK 2.2 web server followed by 250 ns long all atom explicit solvent molecular dynamics simulations. Both the protein and DNA exhibited modest conformational changes with respect to HADDOCK score, energy terms (desolvation energy [Edesolv ]), van der waal energy (Evdw ), electrostatic energy (Eelec ), restraints energy (Eair ), buried surface area, root mean square deviation, RMSF, radius of gyration, total hydrogen bonds when ceftriaxone pre- and postdocked NF-kB conformations were bound to DNA. Hence, the conformational changes in the C-terminal domain could be the reason for EAAT-2 expression through ceftriaxone specific binding pocket of -272 of DNA.

Revisiting the South Indian Traditional Plants against Several Targets of SARS-CoV-2 - An in silico Approach.

BACKGROUND: The south Indian Telugu states will celebrate a new year called 'Ugadi' which is a south Indian traditional festival. The ingredients used in ugadi pachadi have often also been used in food as well as traditional Ayurveda and Siddha medicinal preparations. Coronaviruses (CoVs) are a diverse family of enveloped positive-sense single-stranded RNA viruses which can infect humans and have the potential to cause large-scale outbreaks. OBJECTIVE: Considering the benefits of ugadi pachadi, we investigated the binding modes of various phytochemical constituents reported from its ingredients against five targets of SARS-CoV-2. METHODS: Flexible-ligand docking simulations were achieved through AutoDock version 1.5.6. Following 50ns of molecular dynamics simulation using GROMACS 2018.1 software and binding free energy (ΔGbind) of the protein-ligand complexes were calculated using the g_mmpbsa tool. ADME prediction was done using Qikprop of Schrodinger. RESULTS: From the molecular docking and MM/PBSA results compound Eriodictin exhibited the highest binding energy when complexed with nucleocapsid N protein (6M3M) (-6.8 kcal/mol, - 82.46 kJ/mol), bound SARS-CoV-2-hACE2 complex (6M0J) (-7.4 kcal/mol, -71.10 kJ/mol) and Mpro (6XR3) (-8.6 kcal/mol, -140.21 kJ/mol). Van der Waal and electrostatic energy terms highly favored total free energy binding. CONCLUSION: The compounds Eriodictin, Vitexin, Cycloart-3, 24, 27-triol, Agigenin, Mangiferin, Mangiferolic acid, Schaftoside, 27-Hydroxymangiferonic acid, Quercetin, Azadirachtol, Cubebin, Isomangiferin, Isoquercitrin, Malicarpin, Orientin and procyanidin dimer exhibited satisfactory binding energy values when compared with standard molecules. The further iterative optimization of high-ranked compounds following validation by in vitro and in vivo techniques assists in discovering therapeutic anti-SARS-CoV-2 molecules.

Multiwalled Carbon Nanotubes as Nanomaterial Tool in the Management of Prostate Cancer: A Possible Nanoformulation Approach.

Prostate cancer (PCa) is one of the leading diseases in men all over the world caused due to over-expression of prostate-specific membrane antigen (PSMA). Currently, the detection and targeting of PCa is one of the major challenges in the prostate gland. Therefore, Bruton tyrosine kinase inhibitor molecules like ibrutinib (Ibr) loaded with nanomaterials like multi-walled carbon nanotubes (MWCNTs), which has good physico-chemical properties may be the best regimen to treat PCa. In this strategy, the chemically modified MWCNTs have excellent 'Biosensing' properties makes it easy for detecting PCa without fluorescent agent and thus targets particular site of PCa. In the present study, Ibr/MWCNTs conjugated with T30 oligonucleotide may selectively target and inhibit PSMA thereby reduce the over-expression in PCa. Hence, the proposed formulation design can extensively reduce the dosage regimen without any toxic effect. Additionally, the present hypothesis also revealed the binding mode of Ibr in the catalytic pocket of PSMA by in silico method. Therefore, we presume that if this hypothesis proves correct, it becomes an additional novel tool and one of the conceivable therapeutic options in treating PCa.

Identification of Papain-Like Protease inhibitors of SARS CoV-2 through HTVS, Molecular docking, MMGBSA and Molecular dynamics approach.

Coronaviruses (CoVs) are a large group of enveloped positive sense single-stranded RNA viruses that can cause disease to humans. These are zoonotic having potential to cause large-scale outbreaks of infections widely causing morbidity and mortality. Papain-Like Protease (PLpro) is a cysteine protease, essential for viral replication and proliferation, as a highly conserved enzyme it cleaves peptide linkage between Nsp1, Nsp2, Nsp3, and Nsp4. As a valid therapeutic target, it stops viral reproduction and boosts host immune response thereby halting further spread of infection. In the purpose of identifying inhibitors targeting Papain-Like Proteases (PLpro) we initiated a high throughput virtual screening (HTVS) protocol using a SuperNatural Database. The XP docking results revealed that two compounds SN00334175 and SN00162745 exhibited docking scores of -10.58 kcal/mol and -9.93 kcal/mol respectively. The Further PRIME MMGB-SA studies revealed Van der Waal energy and hydrophobic energy terms as major contributors for total binding free energy. The 100 ns molecular dynamics simulation of SN00334175/7JN2 and SN00162745/7JN2 revealed that these complexes were stabilized with ligand binding forming interactions with Gly266, Asn267, Tyr268, Tyr273, Thr301 and Asp302, Lys157, Leu162, Asp164, Arg166, Glu167, Pro248 and Tyr264.

DFT calculation, molecular docking, and molecular dynamics simulation study on substituted phenylacetamide and benzohydrazide derivatives.

The atomic and molecular properties of the title compounds were calculated by Jaguar using a basis set B3LYP/6-31G**++ with hybrid DFT in the gas phase, to determine the chemical reactivity. Analysis of quantum chemical features such as HOMO and LUMO explained that the electronic charge transfer occurred within the system through conjugated paths of the selected compounds. The nucleophilic and electrophilic reactive sites are recognized from the molecular electrostatic potential plot. Electrophilic and nucleophilic attack-prone molecular sites were predicted by mapping ALIE value to the molecular surface. The bond dissociation energy of the high active compound 15 (2-chloro-N-(2-(2-(2-(2-chlorobenzoyl)hydrazineyl)-2-oxoethoxy)phenyl)acetamide) was calculated to assess the probability of compound autoxidation or degradation. Further, molecular docking, binding free energy calculations, and ADMET profile of the degradation products (DPs) of compound 15 was carried out to determine the binding affinity and toxicity profile of the formed DPs compared with the parent compound. A 150-ns molecular dynamics (MD) simulation was performed to evaluate the binding stability of the compound 15/4URL complex using Desmond. Binding free energy and binding affinity of the complex were computed for 100 trajectory frames using the MM-GBSA approach.

Dipeptidyl peptidase-IV inhibitory action of Calebin A: An in silico and in vitro analysis.

BACKGROUND: Dipeptidyl peptidase-IV (DPP-IV) inhibitors, the enhancers of incretin are used for the treatment of diabetes. The non-glycaemic actions of these drugs (under developmental stage) also proved that repurposing of these molecules may be advantageous for other few complicated disorders like cardiovascular diseases, Parkinson's disease, Alzheimer's disease, etc. OBJECTIVE: The present study was aimed to investigate the DPP-IV inhibitory potential of Calebin-A, one of the constituents of Curcuma longa. MATERIAL AND METHODS: The phytoconstituent was subjected for various in silico studies (using Schrödinger Suite) like, Docking analysis, molecular mechanics combined with generalized Born model and solvent accessibility method (MMGBSA) and Induced fit docking (IFD) after validating the protein using Ramachandran plot. Further, the protein-ligand complex was subjected to molecular dynamic simulation studies for 50 nanoseconds. And finally, the results were confirmed through enzyme inhibition study. RESULTS: Insilico results revealed possible inhibitory binding interactions in the catalytic pocket (importantly Glu205, Glu206 and Tyr 662 etc.) and binding affinity in terms of glide g-score and MMGBSA dG bind values were found to be -6.2 kcal/mol and -98.721 kcal/mol. Further, the inhibitory action towards the enzyme was confirmed by an enzyme inhibition assay, in which it showed dose-dependent inhibition, with maximum % inhibition of 55.9 at 26.3 µM. From molecular dynamic studies (50 nanoseconds), it was understood that Calebin A was found to be stable for about 30 nanoseconds in maintaining inhibitory interactions. CONCLUSION: From the in silico and in vitro analysis, the current research emphasizes the consideration of Calebin A to be as a promising or lead compound for the treatment of several ailments where DPP-IV action is culprit.

Ligand-based pharmacophore modeling and molecular dynamic simulation approaches to identify putative MMP-9 inhibitors.

MMP-9 is a calcium-dependent zinc endopeptidase that plays a crucial role in various diseases and is a ubiquitous target for many classes of drugs. The availability of MMP-9 crystal structure in combination with aryl sulfonamide anthranilate hydroxamate inhibitor facilitates to accentuate the computer-aided screening of MMP-9 inhibitors with the presumed binding mode. In the current study, ligand-based pharmacophore modeling and 3D-QSAR analysis were performed using 67 reported MMP-9 inhibitors possessing pIC50 in the range of 5.221 to 9.000. The established five-point hypothesis model DDHRR_1 was statistically validated using various parameters R 2 (0.9076), Q 2 (0.8170), and F value (83.5) at a partial least square of four. Hypothesis validation and enrichment analysis were performed for the generated hypothesis. Further, Y-scrambling and Xternal validation using mean-absolute error-based criteria were performed to evaluate the reliability of the model. Docking in the XP mode and binding free energy was calculated for 67 selected ligands to explore the key binding interactions and binding affinity against the MMP-9 enzyme. Additionally, high-throughput virtual screening was carried out for 2.3 million chemical molecules to explore the potential virtual hits, and their predicted activity was calculated. Thus, the results obtained aid in developing novel MMP-9 inhibitors with significant activity and binding affinity.

Identification of some novel oxazine substituted 9-anilinoacridines as SARS-CoV-2 inhibitors for COVID-19 by molecular docking, free energy calculation and molecular dynamics studies.

Coronavirus disease (COVID-19), a life-threatening disease, is caused by SARS-CoV-2. The targeted therapeutics of small molecules helps the scientific community to fight against SARS-CoV-2. In this article, some oxazine substituted 9-anilinoacridines (A1-A48) was designed by docking, MM-GBSA and molecular dynamics (MD) simulation studies for their COVID-19 inhibitory activity. The docking of ligands A1-A48 against SARS-CoV-2 (PDB ID: 5R82) are performed by using Glide module, in silico ADMET screening by QikProp module, binding energy using Prime MM-GB/SA module, MD simulation by Desmond module and atomic charges were derived by Jaguar module of Schrodinger suit 2019-4. Compound A38 has the highest G-score (-7.83) when compared to all the standard compounds which are proposed for COVID-19 treatment such as ritonavir (-7.48), lopinavir (-6.94), nelfinavir (-5.93), hydroxychloroquine (-5.47) and mataquine (-5.37). Compounds A13, A23, A18, A7, A48, A46, A32, A20, A1 and A47 are significantly active against SARS-CoV-2 main protease when compared with hydroxychloroquine and mataquine. The residues GLN19, THR24, THR25, THR26, LEU27, HIE41, SER46, MET49, ASN119, ASN142, HIE164, MET165, ASP187, ARG188 and GLN189 of SARS-CoV-2 main protease play a crucial role in binding with ligands. The in silico ADMET properties of the molecules are within the recommended values. The binding free energy was calculated using PRIME MM-GB/SA studies. From the ligands A38, A13, A23, A18, A7, A48 and A46 with significant Glide scores may produce significant COVID-19 activity for further development. Compound A38 was subjected to MD simulation at 100 ns to study the dynamic behaviour of protein-ligand complex.Communicated by Ramaswamy H. Sarma.

A new pyrimidine alkaloid from the roots of Tadehagi triquetrum (L.) H.Ohashi.

Tadehagi triquetrum (L.) H.Ohashi, also known as Desmodium triquetrum (Fabaceae) is the most important plant in the herbal remedies. The present study focus on the isolation, in-silico and in-vitro studies of the two alkaloids C1 (5-(4-[(methylcarbamoyl) amino]-2-oxopyrimidin-1(2H)-yl) tetrahydrofuran-2-yl) methyl methyl carbamate is novel alkaloid and C2 13-Docosenamide is a known alkaloid. The chemical structures of compounds have been elucidated based on comprehensive techniques like GCMS, IR and NMR. In order to know the molecular mechanisms for the two compounds, in silico molecular docking study has been performed. Both compounds have shown perfect binding affinity to the enzymes TNF α, IL-4, IL-13 and 5 LOX Enzyme. The compounds also exhibited comparable G-scores and Glide energy values in comparison with the standard dexamethasone. In addition both the compounds have been tested for in vitro antioxidant assay by using ABTS and DPPH method and the results were compared with standard ascorbic acid.

Identification of Antimycobacterial Agent Using In Silico Virtual Screening, ADME Prediction, Docking, and Molecular Dynamics Simulations Approach.

BACKGROUND: The widespread hazardous issue of antibiotics resistance can be overcome by the development of target based potent antibacterial agents. Filamentous temperature-sensitive mutant Z (FtsZ), a simpler structural prokaryotic homolog of eukaryotic cytoskeletal tubulin, was considered as a competent target in antibacterial drug discovery. OBJECTIVE: The purpose of the present work is to evaluate the antitubercular activity of virtual hits by funnel-shaped filtering with glide docking, followed by MM-GBSA binding energy and molecular dynamics simulation. Pharmacokinetics and biochemical activity of the computationally screened virtual hits have been studied to focus their potential to inhibit the bacterial cell division. METHODS: The docking study was performed against the crystal structure of Staphylococcus aureus and Mycobacterium tuberculosis FtsZ protein with the hits obtained from High Throughput Virtual Screening using the Glide module in Schrodinger. ADME profile and 50 ns molecular dynamics simulation studies were performed using the Schrödinger suite. The minimal inhibitory concentration of the test compounds was determined by the colorimetric method by the Resazurin Microtiter plate Assay. RESULTS: The binding of hit molecules T5427054 and 6M356S was mainly supported by van der Waals interaction and an electrostatic component of solvation energy computed by the MM-GBSA method. 50 ns MD simulation built stability and dynamic property of the best-docked complex T5427054/2Q1Y. Both the hit molecules displayed antimycobacterial activity with minimal inhibitory concentration 500 µg/mL. CONCLUSION: In this study, it is found that new screened hit molecules with better theoretical results could be preferred to use as antimycobacterial agents, and further their structural modification might be improved antimycobacterial properties of hit molecules.

Pharmacophore modeling, atom based 3D-QSAR, molecular docking and molecular dynamics studies on Escherichia coli ParE inhibitors.

ATP dependent ParE enzyme is as an attractive target for the development of antibacterial agents. Atom based 3D-QSAR model AADHR.187 was developed based on the thirty eight Escherichia coli ParE inhibitors. The generated model showed statistically significant coefficient of determinations for the training (R2 = 0.985) and test (R2 = 0.86) sets. The cross-validated correlation coefficient (q2) was 0.976. The utility of the generated model was validated by the enrichment study. The model was also validated with structurally diverse external test set of ten compounds. Contour plot analysis of the generated model unveiled the chemical features necessary for the E. coli ParE enzyme inhibition. Extra-precision docking result revealed that hydrogen bonding and ionic interactions play a major role in ParE protein-ligand binding. Binding free energy was computed for the data set inhibitors to validate the binding affinity. A 30-ns molecular dynamics simulation showed high stability and effective binding of inhibitor 34 within the active site of ParE enzyme. Using the best fitted model AADHR.187, pharmacophore-based high-throughput virtual screening was performed to identify virtual hits. Based on the above studies three new molecules are proposed as E. coli ParE inhibitors with high binding affinity and favourable ADME properties.

Computer-aided identification of lead compounds as Staphylococcal epidermidis FtsZ inhibitors using molecular docking, virtual screening, DFT analysis, and molecular dynamic simulation.

In an effort to face the multiple drug-resistant bacteria, various approaches have been discovered to design potent compounds and search new targets through computational design tools. With an aim to identify selective inhibitors against filamentous temperature-sensitive mutant Z (FtsZ), a library of Phase database compounds have been virtually screened. High-throughput virtual screening of compounds against Staphylococcal epidermidis FtsZ protein (4M8I) was performed using three sequential docking modes like high-throughput virtual screening, Glide standard precision, followed by Glide extra precision. Four top-ranked compounds were selected from molecular mechanics-generalized Born surface area (MM-GBSA) binding energy with better predicted free binding energies of - 89.309, - 54.382, - 53.667, and - 52.133 kcal/mol, respectively. It is also showed that the contribution of van der Waals and electrostatic solvation energy terms are playing a major part to make the hit molecule (T6288784) binding to S. epidermidis FtsZ protein. The result of highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) and energy gap analysis predicts the molecular reactivity and stability of hit molecules. Subsequently, Lipinski's rule of five and properties of absorption, distribution, metabolism, and excretion (ADME) were to calculate their bioavailability. The average binding energy - 9.67 kcal/mol of the best proposed hit molecule (T6288784) was found with half-maximal inhibitory concentration (IC50) value to be 75.53 nM. A 15-ns molecular dynamics simulation study revealed the stable conformation of hit molecule. On a wide-range research discipline, in silico studies of our proposed compound confirm promising results and can be successfully used towards the development of novel FtsZ inhibitor with better binding affinity. Graphical Abstract.