Molecular Mechanics Poisson-Boltzmann Surface Area Research Articles

Targeting Leishmania donovani sterol methyltransferase for leads using pharmacophore modeling and computational molecular mechanics studies

The mortalities and morbidities of leishmaniasis are high and the disease is under reported globally. The absence of vaccines coupled with chemotherapeutic challenges including chemoresistance, scarcity and toxicity have made the fight against leishmaniasis an arduous one. Furthermore, the treatment options currently available for leishmaniasis are long and sometimes require hospitalization. There is therefore the need to explore novel pathways to identify new compounds with alternative mechanisms of action. A pharmacophore-based screening was employed in identifying new potential inhibitors with unique scaffolds targeting Leishmania donovani sterol methyltransferase (LdSMT), a key enzyme for ergosterol biosynthesis. To accomplish this, 22,26-azasterol, a known inhibitor of this target and five other derivatives with IC50 less than 10 μM were used to generate a robust 3D pharmacophore model via LigandScout with a score of 0.9144. The validated model was used as a query to screen a library of 69034 natural products obtained from the InterBioScreen Limited. Compounds with pharmacophore fit scores above 50 were docked against the modelled structure of LdSMT. Altogether, ten molecules with binding energies between −7 and −11 kcal/mol were identified as potential bioactive molecules. The molecular dynamics simulation and molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations reinforced the results from the docking studies suggesting the selected hits bind effectively at the active sites of the target protein. The compounds were observed to bind in the S-adenosine-L-homocysteine binding pocket of the modelled LdSMT with Trp208 and Val330 predicted as key residues critical for ligand binding. Prediction of biological activity with probability of activity (Pa) greater than probability of inactivity (Pi) revealed that seven compounds (STOCKIN-54848, STOCKIN-89115, STOCKIN-68720, STOCKIN-44724, STOCKIN-76694, STOCKIN-47277 and STOCKIN-95708) possessed antileishmanial properties. STOCKIN-89115, STOCKIN-68720, STOCKIN-44724, and STOCKIN-47277 were predicted to be membrane permeability inhibitors, while all ten hit compounds possessed antineoplastic activity. The compounds have the propensity of disrupting ergosterol biosynthesis leading to the suppression of growth in Leishmania donovani. The compounds were predicted to have good absorption, distribution, metabolism, excretion and toxicity profiles, hence their potential antileishmanial activity can be exploited upon experimental corroboration.

Structural-Based Virtual Screening of FDA-Approved Drugs Repository for NSP16 Inhibitors, Essential for SARS-COV-2 Invasion Into Host Cells: Elucidation From MM/PBSA Calculation.

NSP16 is one of the structural proteins of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) necessary for its entrance to the host cells. It exhibits 2'O-methyl-transferase (2'O-MTase) activity of NSP16 using methyl group from S-adenosyl methionine (SAM) by methylating the 5-end of virally encoded mRNAs and shields viral RNA, and also controls its replication as well as infection. In the present study, we used in silico approaches of drug repurposing to target and inhibit the SAM binding site in NSP16 using Food and Drug Administration (FDA)-approved small molecules set from Drug Bank database. Among the 2 456 FDA-approved molecules, framycetin, paromomycin, and amikacin were found to be significant binders against the SAM binding cryptic pocket of NSP16 with docking score of -13.708, -14.997 and -15.841 kcal/mol, respectively. Classical molecular dynamics (MD) simulation and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA)-based binding free energy calculation depicted that all these three framycetin, paromomycin, and amikacin might be promising therapeutic leads towards SARS-CoV-2 infections via host immune escape inhibition pathway.

A molecular dynamics and quantum mechanical investigation of intermolecular interaction and electron-transfer mechanism between copper-containing nitrite reductase and redox partner pseudoazurin.

Much of biological electron transfer occurs between proteins. These molecular processes usually involve molecular recognition and intermolecular electron transfer (inter-ET). The inter-ET reaction between copper-containing nitrite reductase (CuNiR) and partner protein pseudoazurin (PAz) is the first step in denitrification, which is affected by intermolecular association. However, the transient interaction between CuNiR and PAz and the indistinct inter-ET pathway pose challenges for people to understand the biological functions of the CuNiR-PAz complex. Thus, molecular dynamics simulation and quantum mechanical calculation were used to investigate the question in this study. The interaction of the interface residues was determined through hydrogen bonds, root-mean-square deviation, root-mean-square fluctuation, the dynamics cross-correlation matrix, and molecular mechanics Poisson-Boltzmann surface area of molecular dynamics simulations. The interactions among the residues Glu89, Gly200, Asp205, Asn91, Glu204, Thr92, and Met141 on CuNiR and the residues Lys109, Ala15, Lys10, Asn9, Ile110, Met84, and Met16 on PAz are responsible for the stabilization of the complex. The binding free energy is up to -25.33 kcal mol-1. We compared the wild-type and mutant (M84A) interfacial optimized complex models at the CAM-B3LYP level with Grimme dispersion corrections (GD3) to confirm Met84 as a relay station for promoting the inter-ET. Additionally, to test whether Met84 may combine with the adjacent Met141 to form a special two-center, three-electron (S∴S)+ structure to promote the inter-ET, QM/MM was further performed to discuss the possibility of generating an electron stepping stone. Our study will promote a deep understanding of the stable protein-protein interaction, and the identified inter-residue interaction will be theoretical guidance for enhancing the catalytic activity of CuNiR in denitrification.

Bionics design of affinity peptide inhibitors for SARS-CoV-2 RBD to block SARS-CoV-2 RBD-ACE2 interactions

Coronavirus Disease 2019 (COVID-19), has already posed serious threats and impacts on the health of the population and the country's economy. Therefore, it is of great theoretical significance and practical application value to better understand the process of COVID-19 infection and develop effective therapeutic drugs. It is known that the receptor-binding structural domain (SARS-CoV-2 RBD) on the spike protein of the novel coronavirus directly mediates its interaction with the host receptor angiotensin-converting enzyme 2 (ACE2), and thus blocking SARS-CoV-2 RBD–ACE2 interaction is capable of inhibiting SARS-CoV-2 infection. Firstly, the interaction mechanism between SARS-CoV-2RBD-ACE2 was explored using molecular dynamics simulation (MD) coupled with molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) free energy calculation method. The results of energy analysis showed that the key residues R403, R408, K417, and Y505 of SARS-CoV-2 RBD and the key residues D30, E37, D38, and Y41 of ACE2 were identified. Therefore, according to the hotspot residues of ACE2 and their distribution, a short peptide library of high-affinity SARS-CoV-2 RBD was constructed. And by using molecular docking virtual screening, six short peptides including DDFEDY, DEFEDY, DEYEDY, DFVEDY, DFHEDY, and DSFEDY with high affinity for SARS-CoV-2 RBD were identified. The results of MD simulation further confirmed that DDFEDY, DEYEDY, and DFVEDY are expected to be effective inhibitors. Finally, the allergenicity, toxicity and solubility properties of the three peptide inhibitors were validated.

Structure-based pharmacological screening, molecular docking and dynamic simulation reveals Dexketoprofen as a repurposable drug against Alzheimer's disease

Alzheimer's disease (AD) is a progressive, irreversible, neurodegenerative disease that has a profound impact on memory, reasoning, learning, and organizational abilities. Acetylcholinesterase is one of the well-established targets for managing this disease. However, the existing acetylcholinesterase inhibitors are limited in many ways. Hence, in this study, we aimed to identify potential new drugs that can be repurposed to treat AD. For this purpose, an in silico screening of drug molecules that are structural analogues of the three FDA-approved acetylcholinesterase inhibitors donepezil, rivastigmine and galantamine was performed, and 308 analogous compounds were recognized. To find the best possible drug repurposing candidates among them, an extremely rigorous filtering pipeline consisting of several drug-likeness parameters such as Lipinski, Ghose, Veber, Egan, Muegge, lead-likeness, and blood-brain barrier permeability was implemented. Finally, only 61 remained out of the 308 compounds. These 61 compounds then underwent molecular docking against the acetylcholinesterase receptor. Six compounds exhibited a higher binding affinity for the receptor compared to the FDA-approved drugs which were used as controls. Except for one compound that formed unfavorable molecular interactions, the rest were then subjected to sophisticated molecular dynamics simulation and Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) calculation in order to evaluate their binding properties under a simulated physiological environment. Based on all the analyses, we are suggesting Dexketoprofen, a nonsteroidal anti-inflammatory drug as the most promising candidate for repurposing against AD. Our findings will pave the way for narrowing down the list of candidates to be tested in vitro and in vivo in further studies.

Potential inhibitory properties of structurally modified quercetin/isohamnetin glucosides against SARS-CoV-2 Mpro; molecular docking and dynamics simulation strategies

Concerned organizations and individuals are fully engaged in seeking appropriate measures towards managing Severe Acute Respiratory Syndrome Coronavirus 2 (SAR-CoV-2) infection because of the unprecedented economic and health impact. SAR-CoV-2 Main protease (SARS-CoV-2 Mpro) is unique to the survival and viability of the virus. Therefore, inhibition of Mpro can block the viral propagation.Thirty (30) derivatives were built by changing the glucosides in the Meta and para position of quercetin and isohamnetin. Molecular docking analysis was used for the screening of the compounds. Dynamics simulation was performed to assess the stability of the best pose docked complex. Molecular mechanics binding free energy calculation was done by Molecular Mechanics/Poisson-Boltzmann Surface Area (MMPBSA).Overall analysis showed that the compounds are allosteric inhibitors of SARS-CoV-2 Mpro. Dynamic simulation analysis established the stability of Mpro-ISM-1, Mpro-ISD-3, Mpro-IST-2, Mpro-QM-2, and Mpro-QD-6 complexes with a maximum of 7 hydrogen bonds involved in their interaction. The MMPBSA binding free energies for ISM-1, ISD-3, IST-2, QM-2, and QD-6 were −92.47 ± 9.06, −222.27 ± 32.5, 180.72 ± 47.92, 156.46 ± 49.88 and −93.52 ± 48.75 kcal/mol respectively. All the compounds showed good pharmacokinetic properties, while only ISM-1 inhibits hERG and might be cardio-toxic.Observations in this study established that the glucoside position indeed influenced the affinity for SARS-CoV-2 Mpro. The study also suggested the potentials of ISD-3, QM-2 and QD-6 as potent inhibitors of the main protease, further experimental and clinical studies are however necessary to validate and establish the need for further drug development processes. Therefore, future studies will be on the chemical synthesis of the compounds and investigation of the in-vitro inhibition of SARS-CoV-2.

A Novel Inhibitor of DKK1/LRP6 Interactions Against the Alzheimer Disease: An Insilco Approach

The activation of the Wnt signaling pathway is implicated in a neuroprotective mechanism against the Alzheimer disease. When this pathway is blocked, it activates GSK3 beta, leading to tau hyperphosphorylation and the apoptosis of neurons. Dickkopf-related protein 1 (DKK1) is a protein that competes with the Wnt ligand for the low-density lipoprotein receptor–related protein 6 (LRP6) receptor’s binding, interrupting the Wnt-induced Fzd-Wnt-LRP6 complex. This counteracts Wnt’s neuroprotective effect and contributes to the progression of the Alzheimer disease. The aim of this study was to use in silico approach to develop new agents that can combat the Alzheimer disease by targeting the interaction between DKK1 and LRP6. To achieve this, we conducted a virtual screening (Vsw) of the Asinex-CNS database library (n = 54 513) compounds against a generated grid in LRP6 protein. From this screening, we selected 6 compounds based on their docking score and performed molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations on the selected ligands. Next, we evaluated the Absorption, Distribution, Metabolism, and Excretion (ADME) results of the 6 screened compounds using the Quick prop module of Schrödinger. We then employed several computational techniques, including PCA (Principal Component Analysis), DCCM (Dynamic Cross-Correlation Map), molecular dynamics simulation, and molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA)–based negative binding free energy (BFE) calculation, to further analyze the compounds. Our extensive computational analysis resulted in the identification of 3 potential hits, LAS 29757582, LAS 29984441, and LAS 29757942. These compounds were found to block the interaction of DKK1 with LRP6 (A and B interface) protein, and their potential as therapeutic agents was supported by negative BFE calculation. Therefore, these compounds show potential as possible therapeutic agents for treating the Alzheimer disease through targeting the interaction between DKK1 and LRP6.

Molecular docking and dynamics studies show: Phytochemicals from Papaya leaves extracts as potential inhibitors of SARS–CoV–2 proteins targets and TNF–alpha and alpha thrombin human targets for combating COVID-19

<abstract> <p>Tackling COVID-19 requires halting virus proliferation and reducing viral complications in humans. Papaya leaf extract (PLE) is well known for its ability to inhibit numerous viral replications <italic>in vitro</italic> and <italic>in vivo</italic> and reduce viral complications in humans such as thrombocytopenia and cytokine storm. The goal of this research is to evaluate the possible use of papaya leaf extract as a multifaceted antiviral and potential therapy for COVID-19 using an in-silico docking followed by a 100 ns molecular dynamics simulation (MDS) approach. The targeted proteins are the SARS-CoV-2's proteins such as the nucleocapsid, main protease (MPro), RNA-dependent RNA polymerase (RdRP), spike protein (Wuhan, Delta, and Omicron variants) and human TNF-alpha and alpha-thrombin protein targets. Several compounds from PLE such as protodioscin, clitorin, glycyrrhizic acid, manghaslin, kaempferol–3–(2g–glucosylrutinoside), rutin, isoquercetrin and acacic acid were found to exhibit strong binding to these targets. The free energies of binding (Autodock) with protodioscin, the best PLE compound for nucleocapsid, main protease (MPro), RdRP and spike protein were –13.83, –13.19, –11.62 and –10.77 (Omicron), kcal/mol, respectively, while the TNF-alpha and alpha-thrombin binding free energies were –13.64 and –13.50 kcal/mol, respectively. The calculated inhibition constants for protodioscin were in the nanomolar and picomolar range at 216.34, 27.07, 73.28, and 99.93 pM, respectively, whilst RdRp and spike protein (Omicron) were in the nanomolar range at 3.02 and 12.84 nM, respectively. Protodioscin interacted with key residues of all protein targets. The binding affinity poses were confirmed by molecular dynamics simulation. Analysis of the binding affinities calculated employing the molecular mechanics-Poisson–Boltzmann surface area (MM-PBSA) shows favorable interaction between protodioscin, and all targets based on total binding-free energies corroborating the Autodock's docking results. In conclusion, compounds from PLE, especially protodioscin have good potentials in combating COVID-19.</p> </abstract>

Identification of potent COVID-19 main protease inhibitors by loading of favipiravir on Mg12O12 and Zn12O12 nanoclusters: an in silico strategy for COVID-19 treatment

Pandemic new severe acute respiratory syndrome coronavirus (SARS-CoV-2) virus has increased throughout the world. There is no effective treatment against this virus until now. Since its appearance in Wuhan, China in December 2019, SARS-CoV-2 becomes the largest challenge the world is opposite today, including the discovery of an antiviral drug for this virus. Several viral proteins have been prioritized as SARS-CoV-2 antiviral drug targets, among them the papain-like protease (PLpro) and the main protease (Mpro). Inhibition of these proteases would target viral replication, viral maturation and suppression of host innate immune responses. Potential candidates have been identified to show inhibitory effects against Mpro, both in biochemical assays and viral replication in cells. There are different molecules such as lopinavir and favipiravir considerably inhibit the activity of Mpro in vitro. Different studies have shown that structurally improved favipiravir and other similar compounds can inhibit SARS-CoV-2 main protease. In this work, we study the interactions between favipiravir with Mg12O12 and Zn12O12 nanoclusters by density functional theory (DFT) and quantum mechanics atoms in molecules (QMAIM) methods to summarize the ability to load favipiravir onto Mg12O12 and Zn12O12 nanoclusters. Favipiravir-Mg12O12 and favipiravir-Zn12O12 lowest structures complexes were chosen to dock inside the SARS-CoV-2 main protease by molecular docking study. The molecular docking analysis revealed that the binding affinity of Mg12O12 and Zn12O12 nanoclusters inside the Mpro receptor is larger than that of favipiravir. Also, the loading of favipiravir on the surface of Mg12O12 and Zn12O12 nanoclusters increased the binding affinity against the Mpro receptor. Subsequently, 100 ns molecular dynamics simulation of the favipiravir-Mg12O12, and favipiravir-Zn12O12 docked inside the Mpro complexes established that favipiravir-Mg12O12, forms the most stable complex with the Mpro. Further molecular mechanics Poisson Boltzmann surface area (MMPBSA) analyses using the MD trajectories also demonstrated the higher binding affinity of favipiravir-Mg12O12 inside the Mpro. In summary, this study demonstrates a new way to characterize leads for novel anti-viral drugs against SARS-CoV-2, by improving the drug ability of favipiravir via loading it on Mg12O12 and Zn12O12 nanoclusters. Communicated by Ramaswamy H. Sarma

Molecular Insights into the Calcium Binding in Troponin C through a Molecular Dynamics Study

Calcium-binding proteins play critical roles in various biological processes such as signal transduction, cell growth, and transcription factor regulation. Ion binding and target binding of Ca2+-binding proteins are highly related. Therefore, understanding the ion binding mechanism will benefit the relevant inhibitor design toward the Ca2+-binding proteins. The EF-hand is the typical ion binding motif in Ca2+-binding proteins. Previous studies indicate that the ion binding affinity of the EF-hand increases with the peptide length, but this mechanism has not been fully understood. Herein, using molecular dynamics simulations, thermodynamic integration calculations, and molecular mechanics Poisson-Boltzmann surface area analysis, we systematically investigated four Ca2+-binding peptides containing the EF-hand loop in site III of rabbit skeletal troponin C. These four peptides have 13, 21, 26, and 34 residues. Our simulations reproduced the observed trend that the ion binding affinity increases with the peptide length. Our results implied that the E-helix motif preceding the EF-hand loop, likely the Phe99 residue in particular, plays a significant role in this regulation. The E-helix has a significant impact on the backbone and side-chain conformations of the Asp103 residue, rigidifying important hydrogen bonds in the EF-hand and decreasing the solvent exposure of the Ca2+ ion, hence leading to more favorable Ca2+ binding in longer peptides. The present study provides molecular insights into the ion binding in the EF-hand and establishes an important step toward elucidating the responses of Ca2+-binding proteins toward the ion and target availability.

Discovery of octahydropyrrolo [3,2-b] pyridin derivative as a highly selective Type I inhibitor of FGFR3 over VEGFR2 by high-throughput virtual screening.

Although the aberrant activity of fibroblast growth factor receptor 3 (FGFR3) is implicated in various cancers, the reported kinase inhibitors of FGFR3 tend to cause side effects resulting from the inhibitory activity on vascular endothelial growth factor receptor 2 (VEGFR2). Therefore, it is necessary to find a novel high-selective inhibitor of FGFR3 over VEGFR2 from the small-molecule compound database. In this study, integrated virtual screening protocols were established to screen for selective inhibitors of FGFR3 over VEGFR2 in Drugbank and Asinex databases by combining three-dimensional pharmacophore model, molecular docking, molecular dynamics (MD) simulation, and molecular mechanics Poisson-Boltzmann surface area (MMPBSA) calculations. Finally, it is found that Asinex-5082, as an octahydropyrrolo[3,2-b] pyridin derivative, has larger binding free energy with FGFR3 (-39.3 kcal/mol) than reference drug Erdafitinib (-29.9 kcal/mol), while cannot bind with VEGFR2, resulting in considerable inhibitory selectivity. This is because Asinex-5082, unlike Erdafitinib, has not m-dimethoxybenzene with large steric hindrance, thus can enter the larger ATP-binding pocket of FGFR3 with DFG-in conformation to form hydrophobic interaction with residues Met529, Ile539, and Tyr557 as well as hydrogen bond with Ala558. On the other hand, due to the fact that the benzodioxane and N-heterocyclic rings are connected by carbonyl (C=O), Asinex-5082 cannot rotate freely so as to enter the smaller ATPbinding pocket of VEGFR2 on the DFG-out conformation. The lead molecule Asinex-5082 may facilitate the rational design and development of novel selective inhibitors of FGFR3 over VEGFR2 as anticancer drugs.

Virtual Screening of FDA-Approved Drugs for Enhanced Binding with Mitochondrial Aldehyde Dehydrogenase.

Mitochondrial aldehyde dehydrogenase (ALDH2) is a potential target for the treatment of substance use disorders such as alcohol addiction. Here, we adopted computational methods of molecular dynamics (MD) simulation, docking, and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analysis to perform a virtual screening of FDA-approved drugs, hitting potent inhibitors against ALDH2. Using MD-derived conformations as receptors, butenafine (net charge q = +1 e) and olaparib (q = 0) were selected as promising compounds with a low toxicity and a binding strength equal to or stronger than previously reported potent inhibitors of daidzin and CVT-10216. A few negatively charged compounds were also hit from the docking with the Autodock Vina software, while the MM-PBSA analysis yielded positive binding energies (unfavorable binding) for these compounds, mainly owing to electrostatic repulsion in association with a negatively charged receptor (q = -6 e for ALDH2 plus the cofactor NAD+). This revealed a deficiency of the Vina scoring in dealing with strong charge-charge interactions between binding partners, due to its built-in protocol of not using atomic charges for electrostatic interactions. These observations indicated a requirement of further verification using MD and/or MM-PBSA after docking prediction. The identification of key residues for the binding implied that the receptor residues at the bottom and entrance of the substrate-binding hydrophobic tunnel were able to offer additional interactions with different inhibitors such as π-π, π-alkyl, van der Waals contacts, and polar interactions, and that the rational use of these interactions is beneficial to the design of potent inhibitors against ALDH2.

Potential inhibitors of FemC to combat Staphylococcus aureus: virtual screening, molecular docking, dynamics simulation, and MM-PBSA analysis

FemC is a methicillin resistance factor involved in the alterations of peptidoglycan and glutamine synthesis in Staphylococcus aureus. To identify the potent antibacterial agents, antibacterial molecules were screened against the predicted and validated FemC model. Based on docking scores, presence of essential interactions with active site residues of FemC, pharmacokinetic, and ADMET properties, six candidates were shortlisted and subjected to molecular dynamics to evaluate the stability of FemC-ligand complexes. Further, per residue decomposition analysis and Molecular Mechanics/Poisson-Boltzmann Surface Area (MMPBSA) analysis confirmed that S15, M16, S17, R31, R43, Q47, K48 and R49 of FemC played a vital role in the formation of lower energy stable FemC-inhibitor(s) complexes. Therefore, in the present study, the reported six molecules (Z317461228, Z92241701, Z30923155, Z30202349, Z2609517102 and Z92470167) may pave the path to design the scaffold of novel potent antimicrobials against S. aureus. Communicated by Ramaswamy H. Sarma

A Biologically Active Chromone fromBomarea setacea(alstroemeriaceae): Leishmanicidal, Antioxidant and Multilevel Computational Studies

AbstractA chromone was isolated from alcoholic extracts fromBomarea setaceaand identified as 2‐henicosyl‐5,7‐dihydroxy‐4H‐chromen‐4‐one. The leishmanicidal activity was evaluated against intracellular amastigotes ofL. panamensisand cytotoxicity on U‐937 cells, maintained in standard culture conditions. This compound showed leishmanicidal activity (EC50=14.8±1.9 μg/mL, 31.4 μM), low cytotoxicity (LC50=>200 μg/mL, >423.7 μM). Additionally, this compound showed high antioxidant activity through ORAC and DPPH methods. These experimental results motivated us to carry out computational explorations such as docking against several parasite protein targets, molecular dynamics to validate docking results and DFT calculations, used to explain the high antioxidant activity of chromone. Notably, the docking results showed theN‐myristoyltransferase (NMT) enzyme to be a potential target for chromone (docking score −9.1 kcal.mol−1). Molecular dynamics (MD) studies provide strong evidence of the conformational stability of the chromone‐LpNMT complex obtained from docking throughout 50 ns all‐atom MD simulation. Molecular mechanics Poisson‐Boltzmann surface area (MM‐PBSA) analyses of chromone‐LpNMT complex show that the interaction between the ligand and the target protein is stable. DFT calculations allow to explain the greater in vitro antioxidant properties, and drug‐likeness studies show suitable pharmacokinetics properties for chromone. Our findings suggest that chromone has great potential to continue in the search for new drugs to treat leishmaniasis.

Molecular modelling of SdiA protein by selected flavonoid and terpenes compounds to attenuate virulence in Klebsiella pneumoniae

Klebsiella pneumoniae is one of the perturbing multidrug resistant (MDR) and ESKAPE pathogens contributing to the mounting morbidity, mortality and extended rate of hospitalization. Its virulence, often regulated by quorum sensing (QS) reinforces the need to explore alternative and prospective antivirulence agents, relatively from plants secondary metabolites. Computer aided drug discovery using molecular modelling techniques offers advantage to investigate prospective drugs to combat MDR pathogens. Thus, this study employed virtual screening of selected terpenes and flavonoids from medicinal plants to interrupt the QS associated SdiA protein in K. pneumoniae to attenuate its virulence. 4LFU was used as a template to model the structure of SdiA. ProCheck, Verify3D, Ramachandran plot scores, and ProSA-Web all attested to the model’s good quality. Since SdiA protein in K. pneumoniae leads to the expression of virulence, 31 prospective bioactive compounds were docked for antagonistic potential. The stability of the protein-ligand complex, atomic motions and inter-atomic interactions were further investigated through molecular dynamics simulations (MDS) at 100 ns production runs. The binding free energy was estimated using the molecular mechanics/poisson-boltzmann surface area (MM/PB-SA). Furthermore, the drug-likeness properties of the studied compounds were validated. Docking studies showed phytol possesses the highest binding affinity (−9.205 kcal/mol) while glycitein had −9.752 kcal/mol highest docking score. The MDS of the protein in complex with the best-docked compounds revealed phytol with the highest binding energy of −44.2625 kcal/mol, a low root-mean-square deviation (RMSD) value of 1.54 Å and root-mean-square fluctuation (RMSF) score of 1.78 Å. Analysis of the drug-likeness properties prediction and bioavailability of these compounds revealed their conformed activity to lipinski’s rules with bioavailability scores of 0.55 F. The studied terpenes and flavonoids compounds effectively thwart SdiA protein, therefore regulate inter- or intra cellular communication and associated in virulence Enterobacteriaceae, serving as prospective antivirulence drugs. Communicated by Ramaswamy H. Sarma

Evaluation of decursin and its isomer decursinol angelate as potential inhibitors of human glutamate dehydrogenase activity through in silico and enzymatic assay screening

Glutaminolysis is a typical hallmark of malignant tumors across different cancers. Glutamate dehydrogenase (GDH, GLUD1) is one such enzyme involved in the conversion of glutamate to α-ketoglutarate. High levels of GDH are associated with numerous diseases and is also a prognostic marker for predicting metastasis in colorectal cancer. Therefore, inhibiting GDH can be a crucial therapeutic target. Here in this study, we performed molecular docking analysis of 8 different plants derived single compounds collected from pubChem database for screening and selected decursin (DN) and decursinol angelate (DA). We performed molecular dynamics simulation (MD), monitored the stability, interaction for protein and docked ligand at 50 ns, and evaluated the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) free energy calculation on the twoselected compounds along with a standard inhibitor epigallocatechin gallate (EGCG) as reference. The final results showed the formation of stable hydrogen bond interactions by DN and DA in the residues of R400 and Y386 at the ADP activation site of GDH, which was important for the selective inhibition of GDH activity. Additionally, the total binding energy of DN and DA were −115.5 kJ/mol and −106.2 kJ/mol, which was higher than the standard reference GDH inhibitor EGCG (−92.8 kJ/mol). Furthermore, biochemical analysis for GDH inhibition substantiated our computational results and established DN and DA as novel GDH inhibitor. The percentage of IC50 inhibition for DN and DA were 1.035 μM and 1.432 μM. Conclusively, DN and DA can be a novel therapeutic drug for inhibition of glutamate dehydrogenase.

Screening and Identification of Natural Product‐Like Compounds as Potential Antibacterial Agents Targeting FemC of Staphylococcus aureus: An in‐Silico Approach

AbstractFemC is a methicillin resistance factor and regulates the synthesis of peptidoglycan in Staphylococcus aureus. Here, a set of natural product‐like compounds from Enamine and Selleckchem databases were screened at the active site of validated FemC model. Molecules that had interactions and good binding energies with protein were filtered by pharmacokinetic and ADMET properties. Molecular docking and molecular dynamics (MD) analysis displayed the identified molecules had stable and static interactions with FemC to form stable FemC‐inhibitor(s) complexes. Molecular Mechanics/Poisson‐Boltzmann Surface Area (MMPBSA) confirmed that identified molecules interacted with S15, M16, S17, R31, R43, Q47, K48, and R49 of FemC and resulted in the formation of lower energy complexes. The current study, hereby, reported the four (S4958 Glycocholic acid, SP‐146, Hupehenine, and Limonin) potent natural product‐like compounds that are required to be validated and may be further utilized to develop novel scaffolds for antimicrobials against S. aureus.

Structural and vibrational investigations and molecular docking studies of a vinca alkoloid, vinorelbine

Vinorelbine, a vinca alkaloid, is an antimitotic drug that inhibits polymerisation process of tubulins to microtubules, and is widely used in cancer chemotherapy. Due to the importance of the structure-activity relationship, in this work the conformational preferences of the vinorelbine molecule were surched by PM3 method. The obtained lowest energy conformer was then optimized at DFT/B3LYP/6-31G(d,p) level of theory and the structural characteristics were determined. Frontier orbital (HOMO, LUMO) and molecular electrostatic potential (MEP) analyses were performed for the optimized structure. The experimental FT-IR, Raman and UV-VIS spectral data of vinorelbine along with the theoretical DFT/B3LYP/6-31G(d,p) calculations were investigated in detail. The vibrational wavenumbers were assigned based on the calculated potential energy distribution (PED) of the vibrational modes. To shed light into the anticancer property of vinorelbine as microtubule destabilizer, the most favourable binding mode and the interaction details between vinorelbine and tubulin were revealed by molecular docking studies of vinorelbine into the α,β-tubulin (PDB IDs: 4O2B; 1SA0; 7CNN) and binding free energies were calculated by the combination of Molecular Mechanics/Generalized Born Surface Area (MMGBSA) and Molecular Mechanics/Poisson-Boltzmann Surface Area (MM-PBSA) methods {MM/PB(GB)SA}. The calculated vinorelbine-7CNN binding free energy, using by MM/PB(GB)SA approach, was found to be the best (-50.39 kcal/mol), and followed by vinorelbine-4O2B (-28.5 kcal/mol) and vinorelbine-1SA0 (-17.59 kcal/mol) systems. Moreover, the interaction of vinorelbine with the cytochrome P450 enzymes (CYP), which are known to help in the metabolism of many drugs in the body, was investigated by docking studies against CYP2D6 and CYP3A4 targets. Communicated by Ramaswamy H. Sarma

Repurposing of Existing Pharmaceutical Drugs Against Monkey-pox Virus: An In Silico Study

Monkeypox virus (MPXV) is considered as zoonotic disease with characteristics comparable to smallpox virus. The disease is now a global epidemic concern. Currently, tecovirimat is approved by US Food and Drug Administration (FDA) for MPXV treatment. The aim of this in silico study is to repurpose approved pharmaceutical drugs as potential inhibitors of MPXV target. In this study, molecular docking was performed on 406 pharmaceutical drugs, and results were compared with reference tecovirimat. Results showed that 7 compounds, bictegravir, glimepiride, glyburide, lasmiditan, olaparib, rimegepant, and ubrogepant, have shown higher binding energies compared to the reference. After that, these best hits were further assessed by 100 ns molecular dynamics simulation and the best results were observed for bictegravir, glimepiride, glyburide, olaparib, and ubrogepant. The docking analysis was further validated by molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations. In addition, pharmacokinetics and density functional theory (DFT) studies were also discussed for these best hits. In conclusion, three compounds, bictegravir, glimepiride, and glyburide, have satisfied all the criteria for better leads against MPXV.

Finding inhibitors and deciphering inhibitor-induced conformational plasticity in the Janus kinase via multiscale simulations

ABSTRACT The Janus kinase (JAK) is a master regulator of the JAK/STAT pathway. Dysregulation of this signalling cascade causes neuroinflammation and autoimmune disorders. Therefore, JAKs have been characterized as an attractive target for developing anti-inflammatory drugs. Nowadays, designing efficient, effective, and specific targeted therapeutics without being cytotoxic has gained interest. We performed the virtual screening of natural products in combination with pharmacological analyses. Subsequently, we performed molecular dynamics simulations to study the stability of the ligand-bound complexes and ligand-induced inactive conformations. Notably, inactive kinases display remarkable conformational plasticity; however, ligand-induced molecular mechanisms of these conformations are still poorly understood. Herein, we performed a free energy landscape analysis to explore the conformational plasticity of the JAK1 kinase. Leonurine, STOCK1N-68642, STOCK1N-82656, and STOCK1N-85809 bound JAK1 exhibited a smooth transition from an active (αC-in) to a completely inactive conformation (αC-out). Ligand binding induces disorders in the αC-helix. Molecular mechanics Poisson Boltzmann surface area (MM/PBSA) calculation suggested three phytochemicals, namely STOCK1N-68642, Epicatechin, and STOCK1N-98615, have higher binding affinity compared to other ligand molecules. The ligand-induced conformational plasticity revealed by our simulations differs significantly from the available crystal structures, which might help in designing allosteric drugs.