Stability Of Protein-ligand Complexes Research Articles

Design, synthesis, and molecular dynamics simulation studies of quinoline derivatives as protease inhibitors against SARS-CoV-2

A new series of quinoline derivatives has been designed and synthesized as probable protease inhibitors (PIs) against severe acute respiratory syndrome coronavirus 2. In silico studies using DS v20.1.0.19295 software have shown that these compounds behaved as PIs while interacting at the allosteric site of target Mpro enzyme (6LU7). The designed compounds have shown promising docking results, which revealed that all compounds formed hydrogen bonds with His41, His164, Glu166, Tyr54, Asp187, and showed π-interaction with His41, the highly conserved amino acids in the target protein. Toxicity Prediction by Komputer Assisted Technology results confirmed that the compounds were found to be less toxic than the reference drug. Further, molecular dynamics simulations were performed on compound 5 and remdesivir with protease enzyme. Analysis of conformational stability, residue flexibility, compactness, hydrogen bonding, solvent accessible surface area (SASA), and binding free energy revealed comparable stability of protease:5 complex to the protease: remdesivir complex. The result of hydrogen bonding showed a large number of intermolecular hydrogen bonds formed between protein residues (Glu166 and Gln189) and ligand 5, indicating strong interaction, which validated the docking result. Further, compactness analysis, SASA and interactions like hydrogen-bonding demonstrated inhibitory properties of compound 5 similar to the existing reference drug. Thus, the designed compound 5 might act as a potential inhibitor against the protease enzyme. Communicated by Ramaswamy H. Sarma Highlights Quinoline derivatives have been designed as protease inhibitors against SARS-CoV-2. The compounds were docked at the allosteric site of SARS-CoV-2-Mpro enzyme (PDB ID: 6LU7) to study the stability of protein-ligand complex. Docking studies indicated the stable ligand-protein complexes for all designed compounds. The Toxicity Prediction by Komputer Assisted Technology protocol in DS v20.1.0.19295 software was used to evaluate the toxicity of the designed quinoline derivatives. Molecular dynamics studies indicated the formation of stable ligand-Mpro complexes.

Synthesis, biological evaluation and molecular dynamics studies of oxadiazine derivatives as potential anti-hepatotoxic agents

Generally, herbal medicines having remarkable popularity for treating liver ailments, but they are still unacceptable because of the deprivation of herbal drug standardization. Therefore, there is a need for promising synthetic drugs to overcome the critical liver problem. We introduce 1, 3, 4-oxadiazine ring in this study to identify better anti-hepatotoxic agents via a suitable synthetic route. These oxadiazine-based derivatives were structurally confirmed by analytical and spectral data and evaluated for their anti-hepatotoxic potential. Further, in vitro hepatotoxicity studies have been done to check the toxicity level in the synthesized compound. Compounds 5a, 5b, 5c and 9d were selected for further biological evaluation according to in vitro results. After that, CCl4-induced animal model was used to evaluate in vivo anti-hepatotoxicity activity. Compound 5a with 52.99%, 59.3%, 79.34% and 5b with 52.16%, 57.65%, 75.10% revealed to be most promising for reduction in level of SGPT, SGOT and ALKP, respectively. Moreover, it was also observed that the compound 5a with 411.01%, 53.39% and 5b with 378.63%, 48.9% level of albumin and total protein were respectively. The induced-fit docking results of the compounds 5a and 5b reveal some essential binding information and exhibited desirable ADME properties, and obeyed Lipinski's rule of five. In addition, molecular dynamics studies for 100 ns further confirm the protein-ligand complex's stability, supporting the in vitro and in vivo data, and help in establishing the SAR of synthesized compounds. Two compounds, 5a and 5 b, exhibited higher anti-hepatotoxic activity than the standard drug silymarin.

Structure based virtual screening of natural compounds and molecular dynamics simulation: Butirosin as Dipeptidyl peptidase (DPP-IV) inhibitor

Type II diabetes mellitus (T2DM) is a major metabolic disorder resulting in increase in morbidity and mortality rates. Dipeptidyl peptidase-IV (DPP-IV) is a validated and interesting target to develop novel and effective antihyperglycemic agents. Herein, we performed virtual screening of Prestwick library of natural compounds using structure based hierarchical methods to screen the potent compounds. Further, evaluations of dock score along with protein ligand interactions studies were performed. The topmost ranked compound was processed for molecular dynamic simulations (MD simulation) studies for 20 ns. In addition, in silico ADME analysis for the selection of compounds having admissible pharmacokinetic properties has been studied. The results of molecular docking suggest that compound Butirosin showed maximum dock score and binding energy as compared to the standard Alogliptin. MD simulation of DPP-IV-Alogliptin and DPP-IV-Butirosin complexes showed good stability throughout the simulation and RMSD values were 2.25 Å and 2.6 Å respectively. Thus, Butirosin could be the potential drug candidate for DPP-IV inhibition. • Dipeptidyl-peptidase-4 is a promising target for TypeII Diabetes Mellitus. • Computational screening of natural hit(s) for inhibition of DPP-4 enzyme. • Pharmacokinetic parameters for the best hits were obtained by in silico ADME. • Molecular dynamic studies indicate the stability of protein ligand complexes.

Identification of natural compounds (proanthocyanidin and rhapontin) as high-affinity inhibitors of SARS-CoV-2 Mpro and PLpro using computational strategies.

The emergence of a new and highly pathogenic coronavirus (SARS-CoV-2) in Wuhan (China) and its spread worldwide has resulted in enormous social and economic losses. Amongst many proteins encoded by the SARS-CoV-2 genome, the main protease (Mpro) or chymotrypsin-like cysteine protease (3CLpro) and papain-like protease (PLpro) serve as attractive drug targets. We screened a library of 2267 natural compounds against Mpro and PLpro using high throughput virtual screening (HTVS). Fifty top-scoring compounds against each protein in HTVS were further evaluated by standard-precision (SP) docking. Compounds with SP docking energy of ≤ -8.0 kcal/mol against Mpro and ≤ -5.0 kcal/mol against PLpro were subjected to extra-precision (XP) docking. Finally, six compounds against each target proteins were identified and subjected to Prime/MM-GBSA free energy calculations. Compounds with the lowest Prime/MM-GBSA energy were subjected to molecular dynamics simulation to evaluate the stability of protein-ligand complexes. Proanthocyanidin and rhapontin were identified as the most potent inhibitors of Mpro and PLpro, respectively. Analysis of protein-inhibitor interaction revealed that both protein-inhibitor complexes were stabilized by hydrogen bonding and hydrophobic interactions. Proanthocyanidin interacted with the catalytic residues (His41 and Cys145) of Mpro, while rhapontin contacted the active site residues (Trp106, His272, Asp286) of PLpro. The docking energies of proanthocyanidin and rhapontin towards their respective targets were -10.566 and -10.022 kcal/mol. This study's outcome may support application of proanthocyanidin and rhapontin as a scaffold to build more potent inhibitors with desirable drug-like properties. However, it requires further validation by in vitro and in vivo studies.

“Identification of Nafamostat and VR23 as COVID-19 drug candidates by targeting 3CLpro and PLpro"

The sudden increase in the COVID-19 epidemic affected by novel coronavirus 2019 has jeopardized public health worldwide. Hence the necessities of a drug or therapeutic agent that heal SARS-CoV-2 infections are essential requirements. The viral genome encodes a large Polyprotein, further processed by the main protease/ 3C-like protease (3CLpro) and papain-like proteases (PLpro) into 16 nonstructural proteins to form a viral replication complex. These essential functions of 3CLpro and PLpro in virus duplication make these proteases a promising target for discovering potential therapeutic candidates and possible treatment for SARS-CoV-2 infection.This study aimed to screen a unique set of protease inhibitors library against 3CLpro and PLpro of the SARS-CoV-2. A molecular docking study was performed using PyRx to reveal the binding affinity of the selected ligands and molecular dynamic simulations were executed to assess the three-dimensional stability of protein-ligand complexes. The pharmacodynamics parameters of the inhibitors were predicted using admetSAR. The top two ligands (Nafamostat and VR23) based on docking scores were selected for further studies. Selected ligands showed excellent pharmacokinetic properties with proper absorption, bioavailability and minimal toxicity. Due to the emerging and efficiency of remdesivir and dexamethasone in healing COVID-19 patients, ADMET properties of the selected ligands were thus compared with it. MD Simulation studies up to 100 ns revealed the ligands' stability at the target proteins' binding site residues. Therefore, Nafamostat and VR23 may provide potential treatment options against SARS-CoV-2 infections by potentially inhibiting virus duplication though more research is warranted.

Molecular docking studies of phytocompounds of Rheum emodi Wall with proteins responsible for antibiotic resistance in bacterial and fungal pathogens: in silico approach to enhance the bio-availability of antibiotics

Rheum emodi Wall. (Himalayan rhubarb) has many pharmacological activities such as antioxidant, antimicrobial, antiviral, anticancer and wound healing. The present study was aimed to understand if major phytocompounds of Rheum emodi could bind proteins responsible for antibiotic resistance in bacterial and fungal pathogens and enhance the potency of antibiotics. The major phytocompounds of R. emodi (emodin, rhein-13c6 and chrysophenol dimethy ether) were retrieved from the Pubchem and target proteins were retrieved from RCSB protein data bank. The docking study was performed by using AutoDock vina software and Molinspiration, swiss ADME servers were used for the determination of Lipinski rule of 5, drug-likeness prediction respectively, whereas, admetSAR and Protox-II tools were used for toxicity prediction. To study the docking accuracy of protein-ligand complexes, MD simulation for 100 ns was done by using Desmond program version 2.0 (Academic version). Among all the selected phytocompounds, emodin showed the best binding affinity against bacterial (Penicillin binding protein 3, 3VSL and fungal target (cytochrome P450 14 alpha-sterol demethylase 1EA1) with binding energy −8.2 and −8.0 Kcal mol−1 respectively. Similarly, rhein-13C6 showed the best binding affinity against fungal target (n-myristoyl transferase 1IYL) with binding energy −8.0 Kcal mol−1 which is higher than antibacterial and antifungal antibiotics. All the selected phytocompounds also fulfill Lipinski rule, non-carcinogenic and non-cytotoxic in nature. These compounds also showed high LD50 value showing non-toxicity of these phytocompounds. MD simulation studies of phytocompounds (emodin and rhein-13C6) define the stability of protein-ligand complexes with in 100 ns time scale. Communicated by Freddie R. Salsbury

In silico exploration of binding of selected bisphosphonate derivatives to placental alkaline phosphatase via docking and molecular dynamics

Bisphosphonates constitute a group of pyrophosphate analogues therapeutically active against bone diseases. Numerous studies confirm their anticancer and antimetastatic potential as well as ability to relieve pathological pain. Although this is a known class of compounds, many aspects of their action remain unexplained and their new interaction partners are still being discovered. Due to the structural similarity to pyrophosphate, their interaction with pyrophosphate-recognizing enzymes seems to be feasible. In current work, the placental alkaline phosphatase (PLAP) is considered as a potential target for these class of compounds. PLAP is one of the enzymes responsible for degradation of pyrophosphate with high clinical significance. An elevation of PLAP level are considered as a potential cancer marker. An in silico study of complexes formed between selected phosphate derivatives and PLAP was performed. It indicates that all tested compounds: alendronic acid, clodronic acid, etidronic acid, zoledronic acid, imidodiphosphoric acid, pyrophosphoric acid, medronic acid, chloromethylenediphosphonic acid and hypophosphoric acid form a complexes with PLAP, stabilized by hydrogen bonds, hydrophobic and van der Waals interactions. Zoledronic acid, drug used in prevention of bone complications during cancer treatment was found to have the lowest estimated energy of binding (−6.6 kcal/mol). In silico study yielded very low energy of binding also for hypophosphate, equal −6.4 kcal/mol, despite having no identified hydrogen bonds. Subsequent molecular dynamic simulations, followed by molecular mechanics generalized-born surface area with pairwise decomposition calculations confirmed the stability of protein-ligand complexes. The results indicate that selected phosphate derivatives may potentially interact with the enzyme, changing its function, what should be investigated during in vitro studies.

In-silico screening of plant-derived antivirals against main protease, 3CLpro and endoribonuclease, NSP15 proteins of SARS-CoV-2

Novel Coronavirus or SARS-CoV-2 outbreak has developed a pandemic condition all over the world. The virus is highly infectious and spreads by human to human local transmission mode. Till date, there is no vaccination or drugs been approved for the treatment by the World Health Organisation. Henceforth, the discovery of the potential drugs is an urgent and utmost requirement for the medical fraternity. Since, the side effects of plant-derived compounds will be lower compared to synthetic/chemical drugs. The Main protease (3CLpro or NSP5) and endoribonuclease (NSP15) proteins are necessity for viral replication and its survival in the host cell. In the present study, in-silico approach of drug development was used to search for potential antiviral plant-derived compounds as inhibitors against SARS-CoV-2 replication proteins. Eight plant-derived compounds of which the antiviral activity was known and available, and two reported drugs against SARS-CoV-2 selected for the molecular docking analysis. The docking results suggested that bisdemethoxycurcumin, demethoxycurcumin, scutellarin, quercetin and myricetin showed least binding energy, i.e., greater than −6.5 Kcal/mol against 3CLpro and endoribonuclease of SARS-CoV-2. Further studies of ADME-Tox and bioavailability of drugs were also performed that exhibited efficient parameters of drug likeness. Molecular dynamics simulation calculations were performed for the most negative binding affinity of the compound to evaluate the dynamic behavior,and stability of protein-ligand complex. Our findings suggest that these compounds could be potential inhibitors of SARS‐CoV-2 main protease and endoribonuclease. However, further in-vitro and pre-clinical experiments would validate the potential inhibitors of SARS‐CoV‐2 proteins.

Identification of novel Aedes aegypti odorant-binding protein 1 modulators by ligand and structure-based approaches and bioassays

Arboviruses are a group of viruses (e.g. Dengue, Chikungunya and Yellow fever virus) that are transmitted by arthropod vectors, which Aedes aegipty is the vector of main viruses in Americas. This vector is responsible to 2.4 millions of arboviruses cases in Brazil with less than a thousand deaths annually. Despite of epidemiological data, arboviruses treatment is symptomatic and the vaccine control is not effective, which makes the vector control against A. aegipty a promising strategy to diseases control. One way to achieve this goal is to development of A. aegipty sensitive olfactory modulators. Odorant binding protein 1 from A. aegypti (AaegOBP1) is essential in sensory communication, and is the first filter in odorant selection, which makes this target promising to development of new repellents. For this reason, hierarchical virtual screening (ligand-based pharmacophore model and molecular docking) together volatility filter was applied at Sigma-Aldrich database (n = 126.851) to prioritize potential molecules to repellency assays. Three compounds showed adequate stereo-electronic requirements (QFIT> 81.53), score to AaegOBP1 binding site (Score > 36.0) and volatile properties and it was chosen for repellency assays. ZINC00170981 and ZINC00131924 showed a dose-response behavior, while ZINC01621824 did not showed activity in repellency assays. Finally, Molecular Dynamics (MD) was employed to hypothesize the stability of protein-ligand complexes. According to RMSD, RMSF and binding free energy data, ZINC00170981 and ZINC00131924 were able to stabilize AaegOBP1 binding-site during the trajectory by interactions with key residues such as His77, Leu89 and Trp114). Communicated by Ramaswamy H. Sarma

In silico analysis and identification of promising hits against 2019 novel coronavirus 3C-like main protease enzyme

The recent outbreak of the 2019 novel coronavirus disease (COVID-19) has been proved as a global threat. No particular drug or vaccine has not yet been discovered which may act specifically against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and causes COVID-19. For this highly infectious virus, 3CL-like main protease (3CLpro) plays a key role in the virus life cycle and can be considered as a pivotal drug target. Structure-based virtual screening of DrugBank database resulted in 20 hits against 3CLpro. Atomistic 100 ns molecular dynamics of five top hits and binding energy calculation analyses were performed for main protease-hit complexes. Among the top five hits, Nafarelin and Icatibant affirmed the binding energy (g_MMPBSA) of –712.94 kJ/mol and –851.74 kJ/mol, respectively. Based on binding energy and stability of protein-ligand complex; the present work reports these two drug-like hits against SARS-CoV-2 main protease. Communicated by Ramaswamy H. Sarma

Identifying novel inhibitor of quorum sensing transcriptional regulator (SdiA) of Klebsiella pneumoniae through modelling, docking and molecular dynamics simulation

In this study, attempts have been made to identify novel inhibitor(s) of SdiA (a homolog of LuxR transcription regulator) of Klebseilla pneumoniae using various computational techniques. 4LFU was used as a template to model the structure of SdiA. ProCheck, Verify3D, Ramachandran plot scores and ProSA-Web confirmed the good quality of the model as the root mean square deviation (RMSD) between SdiA model, and 4LFU template was estimated to be 0.21 Å. The secondary structural contents of SdiA model were predicted using PDBsum. The only binding site of SdiA was identified (area = 523.083 Å2 and volume = 351.044 Å3) using CASTp. Molecular docking at three different levels [high throughput virtual screening, standard-precision (SP) and extra-precision (XP) dockings] with increasingly stringent conditions was performed using Glide on Selleck’s express pick library (L3600). A total of 61 ligands were found to bind with high affinities to the active site of SdiA. Further, the effect of solvent on protein-ligand interaction was evaluated by performing molecular mechanics-general born surface area (Prime/MM-GBSA). On the basis of Prime/MM-GBSA score, molecular dynamics simulation (50 ns) was performed on the ligand (WAY-390139-A) showing lowest binding energy to confirm the stability of protein-ligand complex. Docking energy and the corresponding binding affinity of WAY-390139-A towards SdiA were estimated to be –13.005 kcal mol–1 and 3.46 × 109 M −1, respectively. Our results confirm that WAY-390139-A binds at the autoinducer binding site of SdiA with high affinity and stability and can be further exploited as potential drug against K. pneumoniae after experimental validation. Communicated by Ramaswamy H. Sarma

Preliminary investigation of drug re-purposing as a direction towards anti-Leishmanial drug discovery

Leishmaniasis is a vector born neglected tropical disease caused by Leishmania parasites and communicated by the bite of female Phlebotomine sandfly. Leishmaniasis is associated with more than 1 billion cases annually. Some of the pharmacological options for treating the disease are pentavalent antimonial, pentamidine, miltefosine and amphotericin B. Drug repurposing is a strategy of identifying new uses of approved or investigational drugs that are outside the scope of the first medical indication. In the current study, we looked for pharmacological alternatives to treat leishmaniasis, with an emphasis on drug repurposing approach. In-silico studies were carried out with the help of Schrodinger software and ZINC database was used as a source. Trypanothione reductase (PDB-2JK6) was selected as target protein and validated by checking the RMSD before docking studies. The outcomes of the study revealed that some of the compounds were active against the selected target. We selected top 5 hit molecules and the top 1 molecule is 5-methoxy tetrahydro folic acid. All the hydrogen bonding, aromatic and Pi-Pi interactions of the moiety with the surrounded amino-acid exhibited a significant docking score of -14.07 kcal/mol, which was almost similar to that of co-crystal ligand -14.60 kcal/mol. The top hit molecule was further selected for molecular dynamics study in order to screen out the stability of protein-ligand complex for 5 ns. After completion of the study, it was observed that the test molecule was in the deeper side of the binding pocket of the target protein and reveled its maximum interactions to stabilize the protein-ligand complex. Further, in-vitro and in-vivo evaluation of these compounds will be required in order to conclude that they will be useful for the leishmanial therapy in the future.

Identification of Potential Dual Negative Allosteric Modulators of Group I mGluR Family: A Shape Based Screening, ADME Prediction, Induced Fit Docking and Molecular Dynamics Approach Against Neurodegenerative Diseases.

Glutamate is the principal neurotransmitter in the human brain that exerts its effects through ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs). The mGluRs are a class of C GPCRs that play a vital role in various neurobiological functions, mGluR1 and mGluR5 are the two receptors distributed throughout the brain involved in cognition, learning, memory, and other important neurological processes. Dysfunction of these receptors can cause neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, X-fragile syndrome, anxiety, depression, etc., hence these receptors are high profile targets for pharmaceutical industries. The objective of our study is to find the novel dual negative allosteric modulators to regulate both mGluR1 and mGluR5. In this study, shape screening protocol was used to find the dual negative allosteric modulators for both mGluR1 and mGluR5 followed by ADME prediction, induced-fit docking (IFD) and molecular dynamics simulations. Further, DFT analysis and MESP studies were carried out for the selected compounds. Around 247 compounds were obtained from the eMolecules database and clustered through the CANVAS module and filtered with ADME properties. Furthermore, IFD revealed that the top four compounds (16059796, 25004252, 4667236 and 11670690) having good protein-ligand interactions and binding free energies. The molecular electrostatic potential of the top compounds shows interactions in the amine group and the oxygen atom in the negative potential regions. Finally, molecular dynamics simulations were performed with all the selected as well as the reported compound 29 indicates that the screened hits have better stability of protein ligand complex. Hence, from the results, it is evident that top hits 16059796, 25004252, 4667236 and 11670690 could be a novel and potent dual negative allosteric modulators for mGluR1 and mGluR5.

Screening of promising molecules against MurG as drug target in multi-drug-resistant-Acinetobacter baumannii - insights from comparative protein modeling, molecular docking and molecular dynamics simulation

The UDP-N-acetylglucosamine-N-acetylmuramyl-(pentapeptide) pyrophosphoryl-undecaprenol N-acetylglucosamine transferase (MurG) is located in plasma membrane which plays a crucial role for peptidoglycan biosynthesis in Gram-negative bacteria. Recently, this protein is considered as an important and unique drug target in Acinetobacter baumannii since it plays a key role during the synthesis of peptidoglycan as well as which is not found in Homo sapiens. In this study, initially we performed comparative protein modeling approach to predict the three-dimensional model of MurG based on crystal structure of UDP-N-acetylglucosamine-N-acetylmuramyl-(pentapeptide) pyrophosphoryl-undecaprenol N-acetylglucosamine transferase (PDB ID: 1F0K) from E.coli K12. MurG model has two important functional domains located in N and C- terminus which are separated by a deep cleft. Active site residues are located between two domains and they are Gly20, Arg170, Gly200, Ser201, Gln227, Phe254, Leu275, Thr276, and Glu279 which play essential role for the function of MurG. In order to inhibit the function of MurG, we employed the High Throughput Virtual Screening (HTVS) and docking techniques to identify the promising molecules which will further subjected into screening for computing their drug like and pharmacokinetic properties. From the HTVS, we identified 5279 molecules, among these, 12 were passed the drug-like and pharmacokinetic screening analysis. Based on the interaction analysis in terms of binding affinity, inhibition constant and intermolecular interactions, we selected four molecules for further MD simulation to understand the structural stability of protein-ligand complexes. All the analysis of MD simulation suggested that ZINC09186673 and ZINC09956120 are identified as most promising putative inhibitors for MurG protein in A. baumannii.Communicated by Ramaswamy H. Sarma

In silico Designing of Novel Inhibitors for Triple Inhibition of Aldose Reductase, Aldose Reductase Like Protein 1, and Aldehyde Reductase.

Cancer is a well-known and well-studied disease. There are environmental as well as genetic factors that trigger cancer. All forms of cancer are associated with the deregulation of genes and proteins. Aldose reductase, Aldose Reductase like protein 1 and Aldehyde Reductase are homologous proteins that are overexpressed in different types of cancer. They are NADPHdependent oxidoreductases. The active site is conserved, thus there is very less substrate specificity among those proteins. In this study, novel molecules targeting the three proteins are designed. LigBuilder V2 software is used to design novel molecules. Molecular docking is performed to study the binding affinity of each ligand towards the targets. Molecular Dynamics Simulation was done to check the stability of protein-ligand complexes in an aqueous environment. Six novel molecules have been designed. The six molecules studied are found to have better in silico affinity than tolrestat (known inhibitor). The designed molecules are predicted to be orally active. Finally, Molecular Dynamics Simulation showed that the protein-ligand complexes are stable in an aqueous environment. New molecules targeting Aldose reductase, Aldose Reductase like protein 1 and Aldehyde Reductase have been designed.

Structural activity (monomer and dimer), spectroscopic analysis, chemical reactivity, fungicidal activity and molecular dynamics simulation of phenyl benzamide fungicides: A combined experimental and theoretical approach

The present study aims to provide deeper knowledge of the structural activity, spectroscopic analysis, chemical reactivity and fungicidal activity of phenyl benzamide fungicides: flutolanil and mepronil based on monomer and dimer model with the aid of experimental and computational methods. The distribution of the vibrational bands are carried out with the help of normal coordinate analysis (NCA). The resulting harmonic wavenumbers are scaled by using Wavenumber Linear Scaling method (WLS). The nature of the hydrogen bonds are characterized by NBO analysis. The evaluated HOMO and LUMO energies indicate the chemical stability of the molecules. The time dependent density functional theory is used to find the various electronic transitions and their nature within the molecule. The molecular orbital contributions are studied by using TDOS spectral analysis. The molecular electrostatic potential (MESP) and global reactivity descriptor parameters are also performed. The 1H and 13C NMR spectra are recorded. The stable conformers of flutolanil and mepronil have been identified by potential energy surface scan analysis. The binding affinity and hydrogen bond interaction between the selected compounds and the target protein are evaluated using molecular docking studies. The pose with highest interaction energy and hydrogen bond interaction is further analyzed using molecular dynamics studies to understand the effect of ligands on conformational changes of protein and the stability of protein ligand complex. The invitro analysis has been performed against two fungal pathogens, Aspergillus niger and Candida albicans.

Coumarin derivatives as acetyl- and butyrylcholinestrase inhibitors: An in vitro, molecular docking, and molecular dynamics simulations study

Alzheimer's disease is an irreversible and progressive brain disease that can cause problems with memory and thinking skills. It is characterized by loss of cognitive ability and severe behavioral abnormalities, and could lead to death. Cholinesterases (ChEs) play a crucial role in the control of cholinergic transmission, and subsequently, the acetylcholine level in the brain is upgraded by inhibition of ChEs. Coumarins have been shown to display potential cholinesterase inhibitory action, where the aromatic moiety has led to the design of new candidates that could inhibit Aβ aggregation. Accordingly, the present work is an in vitro activity, along with docking and molecular dynamics (MD) simulation studies of synthesized coumarin derivatives, to explore the plausible binding mode of these compounds inside the cholinesterase enzymes. For this purpose, a series of previously prepared N1-(coumarin-7-yl) derivatives were screened in vitro for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities. The assayed compounds exhibited moderate inhibitory activity against AChE, with IC50 values ranging from 42.5 ± 2.68 to 442 ± 3.30 μM. On the other hand, the studied compounds showed remarkable activity against BChE with IC50 values ranging from 2.0 ± 1.4 nM to 442 ± 3.30 μM. In order to better understand the ligand binding site interaction of compounds and the stability of protein-ligand complexes, a molecular docking with molecular dynamics simulation of 5000 ps in an explicit solvent system was carried out for both cholinesterases. We concluded that the tested coumarin derivatives are potential candidates as leads for potent and efficacious ChEs inhibitors.

Structure-based design, synthesis and biological evaluation of a newer series of pyrazolo[1,5-a]pyrimidine analogues as potential anti-tubercular agents

In-depth study of structure-based drug designing can provide vital leads for the development of novel, clinically active molecules. In this present study, twenty six novel pyrazolo[1,5-a]pyrimidine analogues (6a-6z) were designed using molecular docking studies. The designed molecules were synthesized in good yields. Structural elucidation of the synthesized molecules was carried out using IR, MS, 1H NMR and 13C NMR spectroscopy. All the synthesized compounds were evaluated for their in-vitro anti-tubercular activity against H37Rv strain by Alamar Blue assay method. Most of the synthesized compounds displayed potent anti-tubercular activities. Amongst all the tested compounds 6p, 6g, 6n and 6h exhibited promising anti-tubercular activity. Further, these potent compounds were gauged for MDR-TB, XDR-TB and cytotoxic study. None of these compounds exhibited potent cytotoxicity. Stability of protein ligand complex was further evaluated by molecular dynamics simulation for 10 ns. All these results indicate that the synthesized compounds could be potential leads for further development of new potent anti-tubercular agents.

Discovery of promising FtsZ inhibitors by E-pharmacophore, 3D-QSAR, molecular docking study, and molecular dynamics simulation

AsbtractFilamentous temperature-sensitive protein Z (FtsZ), playing a key role in bacterial cell division, is regarded as a promising target for the design of antimicrobial agent. This study is looking for potential high-efficiency FtsZ inhibitors. Ligand-based pharmacophore and E-pharmacophore, virtual screening and molecular docking were used to detect promising FtsZ inhibitors, and molecular dynamics simulation was used to study the stability of protein-ligand complexes in this paper. Sixty-three inhibitors from published literatures with pIC50 ranging from 2.483 to 5.678 were collected to develop ligand-based pharmacophore model. 4DXD bound with 9PC was selected to develop the E-pharmacophore model. The pharmacophore models validated by test set method and decoy set were employed for virtual screening to exclude inactive compounds against ZINC database. After molecular docking, ADME analysis, IFD docking and MM-GBSA, 8 hits were identified as potent FtsZ inhibitors. A 50 ns molecular dynamics simulation was implemented on the compounds to assess the stability between potent inhibitors and FtsZ. The results indicated that the candidate compounds had a high docking score and were strongly combined with FtsZ by forming hydrogen bonding interactions with key amino acid residues, and van der Waals forces and hydrophobic interactions had significant contribution to the stability of the binding. Molecular dynamics simulation results showed that the protein-ligand compounds performed well in both the stability and flexibility of the simulation process.

Isozymes inhibited by active site blocking: versatility of calcium indifferent hesperidin binding to phospholipase A2 and its significance

sPLA2 is released under inflammatory conditions from neutrophils, basophils and T-cells. They cleave the cellular phospholipids leading to the release of arachidonic acid and there by provide intermediates for biosynthesis of inflammatory mediators. The focus of this study is on the interaction of hesperidin, a natural flavonoid with Group IB, IIA, and V and X isozymes of sPLA2. Affinity of hesperidin towards PLA2 isozymes was analyzed through enzymatic studies and molecular modeling. The experiments showed that hesperidin competitively inhibited PLA2 with IC50 of 5.1 µM. Molecular modeling studies revealed the association of hesperidin with the docking scores −6.90, −9.53, −5.63 and −8.29 kcal for isozymes Group IB, IIA, V and X of PLA2 respectively. Their binding energy values were calculated as −20.25, −21.63, −21.66 and −33.43 kcal for the Group IB, IIA, V and X respectively. Structural model for Group V was made by homology modeling since no structural coordinates were available. Molecular dynamics studies were carried out to evaluate the structural stability of protein ligand complex. The analyses showed that hesperidin blocked the entry of the substrate to the active site of PLA2 and it was indifferent to the differences of the isozymes. Hence, hesperidin might serve as lead for designing highly specific anti-inflammatory drugs directed to the PLA2 isozyme specific to various diseases, with IC50 value of therapeutic significance.