Poisson-Boltzmann Surface Area Research Articles

Computational insights into pediatric adenovirus inhibitors: in silico strategies for drug repurposing

Human adenovirus (HADV) infection can pose a serious threat to children, leading to a variety of respiratory illnesses and other complications. Particularly, children with weak immune systems are vulnerable to severe adenovirus infections with high mortality. The main focus of this study is to propose new antiviral agents as lead HADV inhibitors for children. So, several antiviral agents used in children were subjected to finding new HADV inhibitors using important computational methods of molecular docking, molecular dynamics (MD) simulation, Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) binding free energy calculations, density functional theory (DFT), and pharmacokinetic analysis. Molecular docking of standard cidofovir along with other ligands, suggested that sofosbuvir has the highest binding energy (−10.8 kcal/mol), followed by baloxavir marboxil (−10.36 kcal/mol). Further, the analysis of molecular interactions using MD simulation (100 ns) and MM-PBSA indicated that baloxavir marboxil has formed the most stable protein–ligand complex with HADV, followed by sofosbuvir. The binding free energies of baloxavir marboxil and sofosbuvir were found to be −61.724 kJ/mol and −48.123 kJ/mol, respectively. The DFT and drug-likeness properties of these compounds were also investigated. Overall, two antiviral agents, such as baloxavir marboxil, and sofosbuvir are suggested as lead repurposed candidates against HADV. Communicated by Ramaswamy H. Sarma

Exploring Quercetin Hydrate’s Potential as an Antiviral Treatment for Oropouche Virus

The Oropouche virus is an orthobunyavirus responsible for causing Oropouche fever, a disease that primarily affects thousands of people in South and Central America. Currently, no specific antiviral treatments or vaccines are available against this virus, highlighting the urgent need for safe, affordable, and effective therapies. Natural products serve as an important source of bioactive compounds, and there is growing interest in identifying natural bioactive molecules that could be used for treating viral diseases. Quercetin hydrate is a compound classified as a flavonoid, which has garnered scientific attention due to its potential health benefits and its presence in various plant-based foods. In this study, we aim to evaluate the in vitro antiviral activity of quercetin hydrate against the Oropouche virus (OROV). Furthermore, we intend to explore its mode of action through in silico approaches. The cytotoxicity and antiviral activity of the compound were assessed using Vero cells. In addition, in silico studies were also performed through molecular docking, molecular dynamics simulations, Molecular Mechanics Poisson–Boltzmann surface area (MM/PBSA), and quantum-mechanical analysis in order to evaluate the interaction with the Gc protein of OROV. The assay revealed that the compound was highly active against the virus, inhibiting OROV with an EC50 value of 53.5 ± 26.5 µM under post-infection treatment conditions. The present study demonstrates that the compound is a promising antiviral agent; however, the mechanisms of action proposed in this study need to be experimentally verified by future assays.

In Silico Discovery of Potential Inhibitors Targeting the RNA Binding Loop of ADAR2 and 5-HT2CR from Traditional Chinese Natural Compounds.

Adenosine deaminase acting on RNA 2 (ADAR2) is an important enzyme involved in RNA editing processes, particularly in the conversion of adenosine to inosine in RNA molecules. Dysregulation of ADAR2 activity has been implicated in various diseases, including neurological disorders (including schizophrenia), inflammatory disorders, viral infections, and cancers. Therefore, targeting ADAR2 with small molecules presents a promising therapeutic strategy for modulating RNA editing and potentially treating associated pathologies. However, there are limited compounds that effectively inhibit ADAR2 reactions. This study therefore employed computational approaches to virtually screen natural compounds from the traditional Chinese medicine (TCM) library. The shortlisted compounds demonstrated a stronger binding affinity to the ADAR2 (<-9.5 kcal/mol) than the known inhibitor, 8-azanebularine (-6.8 kcal/mol). The topmost compounds were also observed to possess high binding affinity towards 5-HT2CR with binding energies ranging from -7.8 to -12.9 kcal/mol. Further subjecting the top ADAR2-ligand complexes to molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations revealed that five potential hit compounds comprising ZINC000014637370, ZINC000085593577, ZINC000042890265, ZINC000039183320, and ZINC000101100339 had favorable binding free energies of -174.911, -137.369, -117.236, -67.023, and -64.913 kJ/mol, respectively, with the human ADAR2 protein. Residues Lys350, Cys377, Glu396, Cys451, Arg455, Ser486, Gln488, and Arg510 were also predicted to be crucial in ligand recognition and binding. This finding will provide valuable insights into the molecular interactions between ADAR2 and small molecules, aiding in the design of future ADAR2 inhibitors with potential therapeutic applications. The potential lead compounds were also profiled to have insignificant toxicities. A structural similarity search via DrugBank revealed that ZINC000039183320 and ZINC000014637370 were similar to naringin and naringenin, which are known adenosine deaminase (ADA) inhibitors. These potential novel ADAR2 inhibitors identified herein may be beneficial in treating several neurological disorders, cancers, viral infections, and inflammatory disorders caused by ADAR2 after experimental validation.

Prediction of Rab5B inhibitors through integrative in silico techniques.

Rab5B is a small monomeric G protein that regulates early endocytosis and controls signaling pathways related to cell growth, survival, and apoptosis. Dysregulation of Rab5B protein expression has been linked to the development of several cancers such as leukemia, lymphoma, kidney, prostate, ovarian, breast cancer, etc. Our research shows the first attempt to identify inhibitors that can target Rab5B GTPase. In this study, we performed molecular docking using Autodock Vina 1.5.6 and identified eight molecules with docking scores ranging from -9.8 to -10.6kcal/mol. Thereafter, we examined the pharmacological characteristics of these compounds, and selected compounds were further analyzed for their conformational dynamics and thermodynamic stability using molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA)-based free energy calculations. Notably, our findings revealed that strychnine had the highest binding affinity to Rab5B followed by anonaine, helioxanthin, and taiwanin E, with a ΔGbind value of -21.43, -17.11, -15.11, and -14.09kcal/mol respectively. The binding free energy calculations showed that Van der Waals interactions are the primary contributor to the binding between Rab5B and the inhibitor. The interaction between the inhibitor and Rab5B was shown to be controlled by certain hot spot residues, including Phe45, Tyr48, Ala64, and Ala30. Overall, we believe that these findings could facilitate the exploration and development of potential hits against Rab5B, subject to optimization and further research. Rab5B inhibitory binding affinity of natural plants active compounds.

Ternary model structural complex of C5a, C5aR2, and β-arrestin1

Complement component fragment 5a (C5a) is one of the potent proinflammatory modulators of the complement system. C5a recruits two genomically related G protein-coupled receptors (GPCRs), like C5aR1 and C5aR2, constituting a binary complex. The C5a-C5aR1/C5aR2 binary complexes involve other transducer proteins like heterotrimeric G-proteins and β-arrestins to generate the fully active ternary complexes that trigger intracellular signaling through downstream effector molecules in tissues. In the absence of structural data, we had recently developed highly refined model structures of C5aR2 in its inactive (free), meta-active (complexed to the CT-peptide of C5a), and active (complexed to C5a) state embedded to a model palmitoyl‐2‐oleoyl‐sn‐glycero‐3‐phosphocholine (POPC) bilayer. Compared to C5aR1, C5aR2 is established as a noncanonical GPCR, as it recruits and signals through β-arrestins rather than G-proteins. Notably, structural understanding of the ternary complex involving C5a-C5aR2-β-arrestin is currently unknown. The current study has attempted to fill the gap by generating a highly refined, fully active ternary model structural complex of the C5a-C5aR2-β-arrestin1 embedded in a model POPC bilayer. The computational modeling, 500 ns molecular dynamics (MD) studies, and the principal component analysis (PCA), including the molecular mechanics Poisson-Boltzmann surface area (MM PBSA) based data presented in this study, provide an experimentally testable hypothesis about C5a-C5aR2-β-arrestin1 extendable to other such ternary systems. The model ternary complex of C5a-C5aR2-β-arrestin1 will further enrich the current structural understanding related to the interaction of β-arrestins with the C5a-C5aR2 system. Communicated by Ramaswamy H. Sarma

A network pharmacology approach to elucidate the anti-inflammatory effects of ellagic acid

Ellagic acid (EA) is a naturally occurring polyphenolic compound found in various fruits and vegetables like strawberries, raspberries, pomegranates, and nuts such as pecans and walnuts. With its antioxidant properties, EA has shown potential health benefits, although further research is necessary to fully comprehend its effects, mechanisms, and safe and effective application as a complementary medicine. Notably, there is accumulating evidence of EA's anti-inflammatory effects; however, the precise underlying mechanism remains unclear. To investigate the anti-inflammatory properties of EA, a network pharmacology approach was employed. The study identified 52 inflammation-related targets of EA and revealed significant signaling pathways and relevant diseases associated with inflammation through GO and KEGG analysis. Furthermore, topological analysis identified 10 important targets, including AKT1, VEGFA, TNF, MAPK3, ALB, SELP, MMP9, MMP2, PTGS2, and ICAM1. Molecular docking and molecular dynamics simulations were conducted, indicating that AKT1, PTGS2, VEGFA, and MAPK3 are the most likely targets of EA, as evidenced by their molecular mechanics Poisson-Boltzmann surface area binding energy calculations. In summary, this study not only confirmed the anti-inflammatory effects of EA observed in previous research but also identified the most probable targets of EA. Communicated by Ramaswamy H. Sarma

Exploring the therapeutic potential of galidesivir analogs against Zaire ebolavirus protein 24 (V24): database screening, molecular docking, drug-relevant property evaluation and molecular dynamics simulations

The recent outbreak of the Ebola virus (EBOV) has marked it as one of the most severe health threats globally. Among various anti-EBOV inhibitors studied, galidesivir (BCX4430) has shown remarkable efficacy. This study aims to identify novel potential anti-EBOV drugs among galidesivir analogs, focusing on the Zaire ebolavirus (Z-EBOV), which exhibits a mortality rate of 90%. We subjected 200 candidate compounds to molecular docking calculations, followed by an evaluation of the bioactivity of the top 25 compounds using the OSIRIS Property Explorer. Initial 50 ns molecular dynamics (MD) simulations were then performed. According to our findings, only six compounds exhibited positive drug scores. We further performed molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations of binding energy over 50 ns, selecting the two top-performing compounds for extended 150 ns MD simulations. CID 117698807 and CID 117712809 showed higher binding stability compared to galidesivir, with ΔG binding values of −36.7 and −53.4 kcal/mol, respectively. Both compounds demonstrated high stability within the Z-EBOV-V24 active site over the 150 ns MD simulations. Hence, our study proposes CID 117698807 and CID 117712809 as potential anti-Z-EBOV-V24 drug candidates, warranting further investigation. Communicated by Ramaswamy H. Sarma

Biological and molecular approaches of the degradation or decolorization potential of the hypersaline Lake Tuz Bacillus megaterium H2 isolate

The presence of synthetic dyes in water bodies and soil is one of the major issues affecting the global ecology, possibly impacting societal well-being adversely due to the colorants’ recalcitrance and toxicity. Herein, the study spectrophotometrically monitored the ability of the Bacillus megaterium H2 azoreductase (AzrBmH2) to degrade four synthetic dyes, reactive blue 4, remazol brilliant red, thymol blue, and methyl red, followed by in-silico assessment using GROMACS. We found that the bacterium degraded as much as 60% of all four synthetic dyes at various tested concentrations. The genome analysis revealed five different azoreductase genes, which were then modeled into the AzrBmH21, AzrBmH22/3, and AzrBmH24/5 templates. The AzrBmH2-substrate complexes showed binding energies with all the dyes of between −10.6 to −6.9 kcal/mol and formed 4–6 hydrogen bonds with the predicted catalytic binding residues (His10, Glu 14, Ser 58, Met 99, Val 107, His 183, Asn184 and Gln 191). In contrast, the lowest binding energies were observed for the AzrBmH21-substrates (−10.6 to −7.9). Molecular dynamic simulations revealed that the AzrBmH21-substrate complexes were more stable (RMSD 0.2–0.25 nm, RMSF 0.05 − 0.3 nm) and implied strong bonding with the dyes. The Molecular Mechanics Poisson-Boltzmann Surface Area results also mirrored this outcome, showing the lowest azoreductase-dye binding energy in the order of AzrBmH21-RB4 (−78.18 ± 8.92 kcal/mol), AzrBmH21-RBR (−67.51 ± 7.74 kcal/mol), AzrBmH21-TB (−46.62 ± 5.23 kcal/mol) and AzrBmH21-MR (−40.78 ± 7.87 kcal/mol). In short, the study demonstrated the ability of the B. megaterium H2 to efficiently decolorize the above-said synthetic dyes, conveying the bacterium’s promising use for large-scale dye remediation. Communicated by Ramaswamy H. Sarma

Dispersion-corrected DFT calculations and umbrella sampling simulations to investigate stability of Chrysin-cyclodextrin inclusion complexes

The study of inclusion complexes of Chrysin (ChR) with three forms of cyclodextrins (CDs) α-, β-, and γ-CD was accomplished to examine the stability of ChR inside the central cavities of CDs. The aim of study was to identify the most suitable form of CD to improve the hydro-solubility of poorly soluble ChR bioactive molecule. Microsecond timescale molecular dynamics (MD) simulations were performed on four inclusion complexes (α-CD/ChR, β-CD/ChR, and two conformations of γ-CD/ChR) to examine the dynamics of ChR inside the cavity of CDs. The first conformation of γ-CD/ChR inclusion complex (γ-CD1/ChR) was identified to possess the highest affinity between host and guest molecule on the basis of binding energy calculated by employing Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) and umbrella sampling simulations. To further strengthen the claims of classical and biased MD studies, Our own N-layered Integrated molecular Orbital and Molecular mechanics (ONIOM) (wB97XD/6–311+g(d,p):pm7) calculations were performed on the selected inclusion complexes. The ONIOM based complexation energy reaffirmed that ChR had highest affinity for the γ-CD1 host molecule. Further, the non-covalent interaction analysis was conducted using Multiwfn software on QM-optimized inclusion complexes with wB97XD/6–311+G(d,p) model chemistry, revealing non-covalent interactions between ChR and CDs. This atomic level information helped us to gain better insights into critical atoms of ChR and CD that participated in intermolecular interactions and identify γ-CD as a suitable host molecule for improving the hydro-solubulity of ChR. The structural insights would help to derive new derivatives of γ-CD with better host capacity.

Establishing the Role of Iridoids as Potential Kirsten Rat Sarcoma Viral Oncogene Homolog G12C Inhibitors Using Molecular Docking; Molecular Docking Simulation; Molecular Mechanics Poisson-Boltzmann Surface Area; Frontier Molecular Orbital Theory; Molecular Electrostatic Potential; and Absorption, Distribution, Metabolism, Excretion, and Toxicity Analysis.

The RAS gene family is one of the most frequently mutated oncogenes in human cancers. In KRAS, mutations of G12D and G12C are common. Here, 52 iridoids were selected and docked against 8AFB (KRAS G12C receptor) using Sotorasib as the standard. As per the docking interaction data, 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester (dock score: -9.9 kcal/mol), 6'-O-trans-para-coumaroyl geniposidic acid (dock score: -9.6 kcal/mol), 6-O-trans-cinnamoyl-secologanoside (dock score: -9.5 kcal/mol), Loganic acid 6'-O-beta-d-glucoside (dock score: -9.5 kcal/mol), 10-O-succinoylgeniposide (dock score: -9.4), Loganic acid (dock score: -9.4 kcal/mol), and Amphicoside (dock score: -9.2 kcal/mol) showed higher dock scores than standard Sotorasib (dock score: -9.1 kcal/mol). These common amino acid residues between iridoids and complexed ligands confirmed that all the iridoids perfectly docked within the receptor's active site. The 100 ns MD simulation data showed that RMSD, RMSF, radius of gyration, and SASA values were within range, with greater numbers of hydrogen bond donors and acceptors. MM/PBSA analysis showed maximum binding energy values of -7309 kJ/mol for 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester. FMO analysis showed that 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester was the most likely chemically reactive molecule. MEP analysis data highlighted the possible electrophilic and nucleophilic attack regions of the best-docked iridoids. Of all the best-docked iridoids, Loganic acid passed Lipinski, Pfizer, and GSK filters with a similar toxicity profile to Sotorasib. Thus, if we consider these iridoids to be KRAS G12C inhibitors, they will be a boon to mankind.

Expression Pattern and Ligand Binding Characteristics Analysis of Chemosensory Protein SnitCSP2 from Sirex nitobei.

Sirex nitobei is an important wood-boring wasp to conifers native to Asia, causing considerable economic and ecological damage. However, the current control means cannot achieve better efficiency, and it is expected to clarify the molecular mechanism of protein-ligand binding for effective pest control. This study analyzed the expression pattern of CSP2 in S. nitobei (SnitCSP2) and its features of binding to the screened ligands using molecular docking and dynamic simulations. The results showed that SnitCSP2 was significantly expressed in female antennae. Molecular docking and dynamic simulations revealed that SnitCSP2 bound better to the host plant volatile (+)-α-pinene and symbiotic fungal volatiles terpene and (-)-globulol than other target ligands. By the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method, the free binding energies of the three complexes were calculated as -44.813 ± 0.189 kJ/mol, -50.446 ± 0.396 kJ/mol, and -56.418 ± 0.368 kJ/mol, and the van der Waals energy was found to contribute significantly to the stability of the complexes. Some key amino acid residues were also identified: VAL13, GLY14, LYS61, MET65, and LYS68 were important for the stable binding of (+)-α-pinene by SnitCSP2, while for terpenes, ILE16, ALA25, TYR26, CYS29, GLU39, THR37, and GLY40 were vital for a stable binding system. We identified three potential ligands and analyzed the interaction patterns of the proteins with them to provide a favorable molecular basis for regulating insect behavioral interactions and developing new pest control strategies.

Identification of new pentapeptides as potential inhibitors of amyloid–β42 aggregation using virtual screening and molecular dynamics simulations

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease mainly characterized by extracellular accumulation of amyloid-β (Aβ) peptide. Previous studies reported pentapeptide RIIGL as an effective inhibitor of Aβ aggregation and neurotoxicity induced by Aβ aggregates. In this work, a library of 912 pentapeptides based on RIIGL has been designed and assessed for their efficacy to inhibit Aβ42 aggregation using computational techniques. The top hit pentapeptides revealed by molecular docking were further assessed for their binding affinity with Aβ42 monomer using MM-PBSA (molecular mechanics Poisson-Boltzmann surface area) method. The MM-PBSA analysis identified RLAPV, RVVPI, and RIAPA, which bind to Aβ42 monomer with a higher binding affinity −55.80, −46.32, and −44.26 kcal/mol, respectively, as compared to RIIGL (ΔGbinding = −41.29 kcal/mol). The residue-wise binding free energy predicted hydrophobic contacts between Aβ42 monomer and pentapeptides. The secondary structure analysis of the conformational ensembles generated by molecular dynamics (MD) depicted remarkably enhanced sampling of helical and no β–sheet conformations in Aβ42 monomer on the incorporation of RVVPI and RIAPA. Notably, RVVPI and RIAPA destabilized the D23–K28 salt bridge in Aβ42 monomer, which plays a crucial role in Aβ42 oligomer stability and fibril formation. The MD simulations highlighted that the incorporation of proline and arginine in pentapeptides contributed to their strong binding with Aβ42 monomer. Furthermore, RVVPI and RIAPA prevented conformational conversion of Aβ42 monomer to aggregation-prone structures, which, in turn, resulted in a lower aggregation tendency of Aβ42 monomer.

Identification of phytochemical inhibitors targeting phosphate acetyltransferase of Mycoplasma genitalium: insights from virtual screening and molecular dynamics studies.

Mycoplasma genitalium (M. genitalium) has evolved as a superbug, and the developing antimicrobial resistancewith just a few treatment options available is an imminentconcern. Due to the emergence of antibiotic resistance, a new antibiotic class or medications are requiredto combat this pathogen. The phosphate acetyltransferase (PTA) enzyme can be a suitable drug target which is essential for M. genitalium survival and involves in acetate metabolism. To efficiently find potent inhibitors, structure-based drug design approaches targeting the PTA of M. genitalium have been established. In this study, the three most potent phytochemical inhibitors were predicted from virtual screening and these are sitostanyl ferulate, beta-sitosterol-beta-D-glucoside, and brassinolide, with binding energies of - 9.66, - 9.60, and - 9.48kcal/mol, respectively. The active site residues Thr-125, Arg-300, Ser-299, Tyr-272, and Lys-273 appear to be critical in binding the three predicted potentinhibitors. The results of the molecular dynamics study indicate that the three predicted phytochemical inhibitors have formed stable bonds with PTA. Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) was utilized for the estimation of binding free energy of PTA-phytochemical complexes. Taken together, the findings of our computational work might aid in the development of possible potential drugsto treat and ameliorate the severity of M. genitalium infection.

Uni-GBSA: an open-source and web-based automatic workflow to perform MM/GB(PB)SA calculations for virtual screening.

Binding free energy calculation of a ligand to a protein receptor is a fundamental objective in drug discovery. Molecular mechanics/Generalized-Born (Poisson-Boltzmann) surface area (MM/GB(PB)SA) is one of the most popular methods for binding free energy calculations. It is more accurate than most scoring functions and more computationally efficient than alchemical free energy methods. Several open-source tools for performing MM/GB(PB)SA calculations have been developed, but they have limitations and high entry barriers to users. Here, we introduce Uni-GBSA, a user-friendly automatic workflow to perform MM/GB(PB)SA calculations, which can perform topology preparation, structure optimization, binding free energy calculation and parameter scanning for MM/GB(PB)SA calculations. It also offers a batch mode that evaluates thousands of molecules against one protein target in parallel for efficient application in virtual screening. The default parameters are selected after systematic testing on the PDBBind-2011 refined dataset. In our case studies, Uni-GBSA produced a satisfactory correlation with the experimental binding affinities and outperformed AutoDock Vina in molecular enrichment. Uni-GBSA is available as an open-source package at https://github.com/dptech-corp/Uni-GBSA. It can also be accessed for virtual screening from the Hermite web platform at https://hermite.dp.tech. A free Uni-GBSA web server of a lab version is available at https://labs.dp.tech/projects/uni-gbsa/. This increases user-friendliness because the web server frees users from package installations and provides users with validated workflows for input data and parameter settings, cloud computing resources for efficient job completions, a user-friendly interface and professional support and maintenance.

Probing some recent natural compounds from Phellinus baumii, Colletotrichum sp. and Ligustrum lucidum as heat shock protein 90 inhibitors

Heat shock protein 90 (HSP90) is one of the most attractive targets for research on cancer treatment, and nowadays, many studies carried out for the development of effective HSP90 inhibitors. In the current study, recently published ten natural compounds have been investigated using computer aided drug design (CADD) approach. The study consists of three parts; (1) density functional theory (DFT) calculations including geometry optimizations, vibrational analyses, and molecular electrostatic potential (MEP) map calculations, (2) molecular docking and molecular dynamics (MD) simulations, and (3) binding energy calculations. In DFT calculations, Becke three-parameter hybrid functional with Lee-Yang-Parr correlation functional (B3LYP) and 6-31 + G(d,p) basis set were used. After performing molecular docking calculations, top-scoring ligand-receptor complexes were subjected to MD simulations for 100 ns to investigate the stability of the ligand-receptor complexes and the interactions in more detail. Finally, in binding energy calculations molecular mechanics with Poisson-Boltzmann surface area (MM-PBSA) method was used. The results showed that five of the investigated ten natural compounds have higher binding affinity to HSP90α than that of reference drug Geldanamycin, and could be promising compounds for future studies. Communicated by Ramaswamy H. Sarma

In silico identification of natural compounds against SARS-CoV-2 main protease from Chinese herbal medicines.

To determine natural compounds with inhibitory effects toward SARS-CoV-2 Mpro from Chinese herbal medicines. ∼1200 natural compounds from 19 Chinese herbal medicines were collected. Computational methods including molecular docking, drug-likeness assessment, molecular dynamics simulation and molecular mechanics Poisson-Boltzmann surface area analysis were combined to obtain potent inhibitors against SARS-CoV-2 Mpro. Top 20 compounds mainly originated from Ranunculus ternatus and Picrasma quassioides exhibited low binding free energies which below -9.0 kcal/mol. Compounds Japonicone G and Picrasidine T were obtained with favorable drug-likeness. Moreover, the complex of Japonicone G and Mpro had prominent stability. Natural compound Japonicone G is highly promising as a potent inhibitor against SARS-CoV-2 for further study.

Investigating the novel-binding site of RPA2 on Menin and predicting the effect of point mutation of Menin through protein–protein interactions

Protein–protein interactions (PPIs) play a critical role in all biological processes. Menin is tumor suppressor protein, mutated in multiple endocrine neoplasia type 1 syndrome and has been shown to interact with multiple transcription factors including (RPA2) subunit of replication protein A (RPA). RPA2, heterotrimeric protein required for DNA repair, recombination and replication. However, it’s still remains unclear the specific amino acid residues that have been involved in Menin-RPA2 interaction. Thus, accurately predicting the specific amino acid involved in interaction and effects of MEN1 mutations on biological systems is of great interests. The experimental approaches for identifying amino acids in menin-RPA2 interactions are expensive, time-consuming, and challenging. This study leverages computational tools, free energy decomposition and configurational entropy scheme to annotate the menin-RPA2 interaction and effect on menin point mutation, thereby proposing a viable model of menin-RPA2 interaction. The menin–RPA2 interaction pattern was calculated on the basis of different 3D structures of menin and RPA2 complexes, constructed using homology modeling and docking strategy, generating three best-fit models: Model 8 (− 74.89 kJ/mol), Model 28 (− 92.04 kJ/mol) and Model 9 (− 100.4 kJ/mol). The molecular dynamic (MD) was performed for 200 ns and binding free energies and energy decomposition analysis were calculated using Molecular Mechanics Poisson–Boltzmann Surface Area (MM/PBSA) in GROMACS. From binding free energy change, model 8 of Menin-RPA2 exhibited most negative binding energy of − 205.624 kJ/mol, followed by model 28 of Menin-RPA2 with − 177.382 kJ/mol. After S606F point mutation in Menin, increase of BFE (ΔGbind) by − 34.09 kJ/mol in Model 8 of mutant Menin-RPA2 occurs. Interestingly, we found a significant reduction of BFE (ΔGbind) and configurational entropy by − 97.54 kJ/mol and − 2618 kJ/mol in mutant model 28 as compared the o wild type. Collectively, this is the first study to highlight the configurational entropy of protein–protein interactions thereby strengthening the prediction of two significant important interaction sites in menin for the binding of RPA2. These predicted sites could be vulnerable for structural alternation in terms of binding free energy and configurational entropy after missense mutation in menin.

Determination of potential combination of non-β-lactam, β-lactam, and β-lactamase inhibitors/β-lactam enhancer against class D oxacillinases producing Acinetobacter baumannii: Evidence from in-vitro, molecular docking and dynamics simulation.

Carbapenem-resistant Acinetobacter baumannii, a predominant nosocomial pathogen in hospitals of intensive care units, is associated with bacteremia and ventilator-associated pneumonia with a high-risk mortality rate. To increase the effectiveness of the β-lactam (BL) antibiotics, the use of β-lactamase inhibitors (BLI) acts as a booster when given in combination with BL antibiotics. To this aspect, we selected BL antibiotics of cefiderocol, cefepime, non-BL antibiotic eravacycline, BLI of durlobactam, avibactam, and a β-lactam enhancer (BLE) of zidebactam. To prove our hypothesis, we determined the minimum inhibitory concentration (MIC) of various BL or non-BL/BLI or BLE combinations using broth microdilution method followed by in silico analysis of molecular docking, molecular dynamics (MD) simulation, and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) identifies the potential combination. In MIC testing, eravacycline, cefepime/zidebactam, cefiderocol/zidebactam, and eravacycline in combination with zidebactam or durlobactam were found to be effective against oxacillinases (OXAs) (OXA-23/24/58 like) expressing A. baumannii isolates. The docking results of the selected ligands toward OXA-23, OXA-24, and OXA-58 had an excellent binding score ranging from -5.8 to -9.3 kcal/mol. Further, the docked complexes were subjected and evaluated using gromacs for molecular dynamics simulation of 50 ns toward selected class D OXAs. The binding energies obtained from MM-PBSA shed light on the binding efficiencies of each non-BL, BL, and BLI/BLE, thereby helping us to propose the drug combinations. Based on the MD trajectories scoring acquired, we propose using eravacycline, cefepime/zidebactam, cefiderocol/zidebactam, and eravacycline in combination with durlobactam or zidebactam would be promising for treating OXA-23, OXA-24, and OXA-58 like expressing A. baumannii infections.

In silico analysis of the different variable domain oriented single-chain variable fragment antibody-antigen complexes

Single-chain variable fragment (scFv) antibodies hold great potential as diagnostic tools and therapeutic agents, especially for tumor cells. Since these applications require their production with improved properties, the design strategy of scFvs is crucial for their active, soluble, and high yield expression with high affinity towards their antigens. The order of VL and VH domains is one of the important parameters that affect the expression and binding affinity properties of scFvs. In addition, the optimum order of VL and VH domains could change for each scFv. In the present study, we used computer simulation tools to evaluate the effect of variable domain orientation on structure, stability, interacting residues of scFvs, and binding free energies of scFv-antigen complexes. We selected anti-HER2 scFv, which is specific for human epidermal growth receptor 2 (HER2) overexpressed in breast cancer, and anti-IL-1β scFv against IL-1β which is an important inflammatory biomarker, as model scFvs. Molecular dynamics simulations of the scFv-antigen complexes for 100 ns resulted in stability and compactness for both scFv constructs. Interaction and binding free energies calculated by the Molecular Mechanics–Poisson–Boltzmann Surface Area (MM-PBSA) approach suggested that the relative binding energies of anti-HER2 scFv-VLVH and anti-HER2 scFv-VHVL constructs had similar binding affinity towards HER2, while a relatively more negative binding free energy obtained between anti-IL-1β scFv-VHVL and IL-1β pointed to a higher binding affinity. The in silico approach and the results obtained here could be applied as a guide for future experimental interaction studies for highly specific scFvs used as biotechnological tools. Communicated by Ramaswamy H. Sarma

Design of a novel multi-epitope vaccine candidate against Chlamydia trachomatis using structural and nonstructural proteins: an immunoinformatics study

Chlamydia trachomatis (C. trachomatis) is an obligate intracellular bacterium which causes eye and sexually transmitted infections. During pregnancy, the bacterium is associated with preterm complications, low weight of neonates, fetal demise and endometritis leading to infertility. The aim of our study was design of a multi-epitope vaccine (MEV) candidate against C. trachomatis. After protein sequence adoption from the NCBI, potential epitopes toxicity, antigenicity, allergenicity, MHC-I and MHC-II binding, cytotoxic T lymphocytes (CTLs), Helper T lymphocytes (HTLs) and interferon-γ (IFN-γ)- induction were predicted. The adopted epitopes were fused together using appropriate linkers. In the next step, the MEV structural mapping and characterization, three-dimensional (3D) structure homology modeling and refinement were also performed. The MEV candidate interaction with the toll-like receptor 4 (TLR4) was also docked. The immune responses simulation was assessed using the C-IMMSIM server. Molecular dynamic (MD) simulation verified the structural stability of the TLR4-MEV complex. The Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) approach demonstrated the MEV high affinity of binding to the TLR4, MHC-I and MHC-II. The MEV construct was also stable and water soluble and had enough antigenicity and lacked allergenicity with stimulation of T cells and B cells and INF-γ release. The immune simulation confirmed acceptable responses of both the humoral and cellular arms. It is proposed that in vitro and in vivo studies are needed to evaluate the findings of this study. Communicated by Ramaswamy H. Sarma