Molecular Mechanics Poisson-Boltzmann Surface Area Research Articles

Improving the Performance of Screening MM/PBSA in Protein-Ligand Interactions via Machine Learning

Abstract Accurately estimating protein-ligand binding free energy is crucial for drug design and biophysics, yet remains a challenging task. In this study, we applied the screening molecular mechanics/Poisson Boltzmann surface area (MM/PBSA) method in combination with various machine learning techniques to compute the binding free energies of protein-ligand interactions. Our results demonstrate that machine learning outperforms direct screening MM/PBSA calculations in predicting protein-ligand binding free energies. Notably, the random forest (RF) method exhibited the best predictive performance, with a Pearson correlation coefficient (r p ) of 0.702 and a mean absolute error (MAE) of 1.379 kcal/mol. Furthermore, we analyzed feature importance rankings in the gradient boosting (GB), adaptive boosting (AdaBoost), and RF methods, and found that feature selection significantly impacted predictive performance. In particular, molecular weight (MW) and van der Waals (VDW) energies played a decisive role in the prediction. Overall, this study highlights the potential of combining machine learning methods with screening MM/PBSA for accurately predicting binding free energies in biosystems.

Molecular and energetic analysis of the interaction and specificity of Maximin 3 with lipid membranes: In vitro and in silico assessments.

In this study, the interaction of antimicrobial peptide Maximin 3 (Max3) with three different lipid bilayer models was investigated to gain insight into its mechanism of action and membrane specificity. Bilayer perturbation assays using liposome calcein leakage dose-response curves revealed that Max3 is a selective membrane-active peptide. Dynamic light scattering recordings suggest that the peptide incorporates into the liposomal structure without producing a detergent effect. Langmuir monolayer compression assays confirmed the membrane inserting capacity of the peptide. Attenuated total reflection-Fourier transform infrared spectroscopy showed that the fingerprint signals of lipid phospholipid hydrophilic head groups and hydrophobic acyl chains are altered due to Max3-membrane interaction. On the other hand, all-atom molecular dynamics simulations (MDS) of the initial interaction with the membrane surface corroborated peptide-membrane selectivity. Peptide transmembrane MDS shed light on how the peptide differentially modifies lipid bilayer properties. Molecular mechanics Poisson-Boltzmann surface area calculations revealed a specific electrostatic interaction fingerprint of the peptide for each membrane model with which they were tested. The data generated from the in silico approach could account for some of the differences observed experimentally in the activity and selectivity of Max3.

Oleanolic acid purified from the stem bark of Olax subscorpioidea Oliv. inhibits the function and catalysis of human 17β-hydroxysteroid dehydrogenase 1

Cancer is a leading cause of global death. Medicinal plants have gained increasing attention in cancer drug discovery. In this study, the stem bark extract of Olax subscorpioidea, which is used in ethnomedicine to treat cancer, was subjected to phytochemical investigation leading to the isolation of oleanolic acid (OA). The structure was elucidated by 1-dimensional and 2-dimensional nuclear magnetic resonance spectroscopic (NMR) data, and by comparing its data with previously reported data. Molecular docking was used to investigate the interactions of OA with nine selected cancer-related protein targets. OA docked well with human 17β-hydroxysteroid dehydrogenase type-1 (17βHSD1), caspase-3, and epidermal growth factor receptor tyrosine kinase (binding affinities: −9.8, −9.3, and −9.1 kcal/mol, respectively). OA is a triterpenoid compound with structural similarity to steroids. This similarity with the substrates of 17βHSD1 gives the inhibitor candidate an excellent opportunity to bind to 17βHSD1. The structural and functional dynamics of OA-17βHSD1 were investigated by molecular dynamics simulations at 240 ns. Molecular mechanics/Poisson-Boltzmann surface area (MMPBSA) studies showed that OA had a binding free energy that is comparable with that of vincristine (–52.76, and −63.56 kcal/mol, respectively). The average C-α root mean square of deviation (RMSD) value of OA (1.69 Å) compared with the unbound protein (2.01 Å) indicated its high stability at the protein’s active site. The binding energy and stability at the active site of 17βHSD1 recorded in this study indicate that OA exhibited profound inhibitory potential. OA could be a good scaffold for developing new anti-breast cancer drugs.

Deciphering the 4',7-Dihydroxy-3'-Methylflavone from Boerhavia, Agonist/Antagonist Interactions Against 5-HT2 Receptors using Homology Modeling, Molecular Docking, and Dynamic Simulation Studies.

Seizures, depression, and anxiety are neurological disorders that affected innumerable people worldwide. Recent research has revealed that targeting 5-hydroxytryptamine 2 (5-HT2) receptors can help suppress these conditions. An in-depth literature study has identified that phytocompounds from the Boerhavia genus could reduce seizures. Therefore, homology models of 5-HT2 receptors were generated and validated using techniques such as the alignment of amino acid sequences and the Ramachandran plot. Later, a comparison of modeled structures was made with a non-redundant set of PDB structures. The pharmacokinetics, drug-likeness, blood-brain barrier (BBB) permeability, and Lipinski's rule of five shed light on 22 phytocompounds, which are the potential candidates for molecular docking among 127 Boerhavia's bioactive. Notably, molecular docking analysis revealed 4',7-dihydroxy-3'-methylflavone as the most potent lead compound, which has a strong binding affinity to all modeled receptors. Additionally, with a remarkably high docking score of -9.1 kcal/mol, 4',7-dihydroxy-3'-methylflavone showed promising interactions, particularly with 5-HT2A receptor, as seen from the RMSD, SASA, Rg, and number of hydrogen bonds during 100 ns molecular dynamic (MD) simulation. Principal component analysis (PCA) and Molecular Mechanics-Poisson-Boltzmann Surface Area (MM-PBSA) further confirmed that 4',7-dihydroxy-3'-methylflavone is the best novel phytocompound in Boerhavia genus for 5-HT2 receptor as agonist/antagonist activity against seizures.

Structural and dynamical insights revealed the anti-glioblastoma potential of withanolides from Withania coagulans against vascular endothelial growth factor receptor (VEGFR).

Glioblastoma (GBM), well known as grade 4 tumors due to its progressive malignant features such as vascular proliferation and necrosis, is the most aggressive form of primary brain tumor found in adults. Mutations and amplifications in the vascular endothelial growth factor receptor (VEGFR) contribute to almost 25% of GBM tumors. And thus, VEGFR has been declared the primary target in glioblastoma therapeutic strategies. However, many studies have been previously reported that include GBM as global therapeutics challenge, but they lack the molecular level insights that could help in understanding the biological function of a therapeutically important protein playing a major role in the disease and design the best strategies to develop the potential drugs. Therefore, to the best of our knowledge, the present study is the first time of kind, which involves multi-in silico approaches to predict the inhibition potential of withanolides from Withania coagulan against VEGFR. The study is actually based on determining the mode of action of five isolates: withanolide J, withaperuvin, 27-hydroxywithanolide I, coagule E, and coagule E, along with their respective binding energies. Molecular docking simulations revealed primarily four ligands, withanolide J (- 7.33kJ/mol), 27-withanolide (- 7.01kJ/mol), ajugine, withaperuvin (- 6.89kJ/mol), and ajugine E (- 6.39kJ/mol), to have significant binding potencies against the protein. Ligand binding was found to enhance the confirmational stability of the protein revealed through RMSD analysis, and RMSF assessment revealed the protein residues especially from 900-1000 surrounding the binding of the protein. Structural and dynamics of the protein via dynamics cross-correlation movement (DCCM) and principal component analysis (PCA) in both the unbound form and complexed with most potent ligand, withanolide J, reveal the ligand binding affecting the entire conformational integrity of the protein stabilized by hydrogen bonds and electrostatic attractions. Free energy of binding estimations by means of molecular mechanics Poisson-Boltzmann surface area (MMPBSA) method further revealed the withanolide J to have maximum binding potency of the all ligands. Withanolide J in final was also found to have suitable molecular characterizations to cross the blood-brain barrier (BBB +) and reasonable human intestinal absorption ability determined by ADMET profiling via admetSAR tools.

Estimation of Bond Free Energy with Gmx_Mmpbsa in Ndm-1 Complexes

We report the values obtained for the binding free energies (ΔGbind) of the complexes: NDM-1-M25 (43.80 kcal/mol), NDM-1-M26 (12.71 kcal/mol), NDM-1-M35 (19.92 kcal/mol), NDM-1-M37 (2.46 kcal/mol) and the reference system NDM-1-Meropenem (-10.09 kcal/mol). These results are based on previous absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, docking, and molecular dynamics calculations performed on a small library of potential NDM-1 enzyme inhibitors reported in the literature. Subsequently, the selected systems were evaluated by the Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) method using the gmx_MMPBSA software. The MMPBSA method has been widely adopted to estimate protein-ligand binding affinities due to its efficiency and high correlation with experimental data. The obtained results suggest that, unlike the reference complex, the studied ligands probably do not bind to the receptor under the simulation conditions, which is in significant agreement with experimental data.

Targeting PilA in Acinetobacter baumannii: A Computational Approach for Anti-Virulent Compound Discovery.

Acinetobacter baumannii (A. baumannii) has emerged as a critical global pathogen due to its ability to acquire resistance traits. This bacterium exhibits two distinct forms of motility: twitching, mediated by type IV pili (T4P), and surface-associated motility, independent of appendages. T4P is crucial in various bacterial species, facilitating twitching motility, biofilm formation, and host-cell adhesion. The synthesis of T4P is a common feature among Gram-negative pathogens, particularly A. baumannii, suggesting that PilA could be a viable target for biofilm-related treatments. This study aims to develop drug molecules to mitigate A. baumannii virulence by targeting PilA. Using Schrodinger software, we screened 60,766 compounds from the CMNPD, ChemDiv, and Enamine antibacterial databases through high-throughput virtual screening. The top two compounds from each database, identified through extra precision (XP) mode, were subjected to further studies. Among the six compounds identified (CMNPD18469, CMNPD20698, Z2377302405, Z2378175729, N039-0021, and N098-0051), docking scores ranged from -5.0 to -7.5kcal/mol. Subsequently, we conducted 300ns molecular dynamics simulations and Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) analysis of the PilA-ligand complexes. Analysis of the simulation trajectories indicated structural stability and consistent behavior of the PilA-ligand complexes in a dynamic environment. Notably, the PilA-N098-0051 complex exhibited enhanced stability and robust binding interactions, underscoring its potential as a therapeutic agent. These findings suggest that the identified compounds, particularly N098-0051, hold promise as potent molecules targeting PilA, necessitating further validation through in vitro and in vivo studies.

Identification of Novel PPARγ Partial Agonists Based on Virtual Screening Strategy: In Silico and In Vitro Experimental Validation.

Thiazolidinediones (TZDs) including rosiglitazone and pioglitazone function as peroxisome proliferator-activated receptor gamma (PPARγ) full agonists, which have been known as a class to be among the most effective drugs for the treatment of type 2 diabetes mellitus (T2DM). However, side effects of TZDs such as fluid retention and weight gain are associated with their full agonistic activities toward PPARγ induced by the AF-2 helix-involved "locked" mechanism. Thereby, this study aimed to obtain novel PPARγ partial agonists without direct interaction with the AF-2 helix. Through performing virtual screening of the Targetmol L6000 Natural Product Library and utilizing molecular dynamics (MD) simulation, as well as molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analysis, four compounds including tubuloside b, podophyllotoxone, endomorphin 1 and paliperidone were identified as potential PPARγ partial agonists. An in vitro TR-FRET competitive binding assay showed podophyllotoxone displayed the optimal binding affinity toward PPARγ among the screened compounds, exhibiting IC50 and ki values of 27.43 µM and 9.86 µM, respectively. Further cell-based transcription assays were conducted and demonstrated podophyllotoxone's weak agonistic activity against PPARγ compared to that of the PPARγ full agonist rosiglitazone. These results collectively demonstrated that podophyllotoxone could serve as a PPARγ partial agonist and might provide a novel candidate for the treatment of various diseases such as T2DM.

Computational exploration of novel ketoprofen derivatives: Molecular dynamics simulations and MM-PBSA calculations for COX-2 inhibition as promising anti-inflammatory drugs

Computer-aided drug design is widely employed to identify novel compounds for therapeutic applications. Ketoprofen (KTP), a commonly used and marketed nonsteroidal anti-inflammatory drug (NSAID), is effective in treating pain, fever, inflammation, and some cancers. In this research, we explored the behavior of six analogues designed by structurally modifying the KTP molecule. Specifically, KTP-A and KTP-B contain a –CN group at the ortho position, KTP-C and KTP-D have a –CN group at the meta position, and KTP-E and KTP-F feature a –CF3 group at the meta position. To assess these analogues, we conducted molecular dynamics simulations (MD) to study their inhibitory effects on human cyclooxygenase 2 (COX-2), providing detailed insights into the structure and dynamics of the protein both with and without ligands. MD simulation, enhanced by technological advances, has proven to be a powerful tool for new drug discovery. We further quantified the binding affinity of these drug molecules toward COX-2 using molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations. The dynamic properties were evaluated through analyses of root mean square deviations (RMSD), root mean square fluctuations (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA), covariance matrix, principal component analysis (PCA), and Gibbs free energy landscapes (FEL). Ultimately, this study confirms that the six KTP derivatives are promising candidates for the treatment of inflammation, with KTP-B standing out as particularly effective.

Leukotriene B4 receptor 1 (BLT1) activation by leukotriene B4 (LTB4) and E resolvins (RvE1 and RvE2)

Leukotriene B4 (LTB4) is a lipid inflammatory mediator derived from arachidonic acid (AA). Leukotriene B4 receptor 1 (BLT1), a G protein-coupled receptor (GPCR), is a receptor of LTB4. Nonetheless, the resolution of inflammation is driven by specialized pro-resolving lipid mediators (SPMs) such as resolvins E1 (RvE1) and E2 (RvE2). Both resolvins are derived from omega-3 fatty acid eicosapentaenoic acid (EPA). Here, long-term molecular dynamics simulations (MD) were performed to investigate the activation of the BLT1 receptor using two pro-resolution agonists (RvE1 and RvE2) and an inflammatory agonist (LTB4). We have analyzed the receptor's activation state, electrostatic interactions, and the binding affinity the Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) approach. The results showed that LTB4 and RvE1 have kept the receptor in an active state by higher simulation time. MD showed that the ligand-receptor interactions occurred mainly through residues H94, R156, and R267. The MMPBSA calculations showed residues R156 and R267 were the two mainly hotspots. Our MMPBSA results were compatible with experimental results from other studies. Overall, the results from this study provide new insights into the activation mechanisms of the BLT1 receptor, reinforcing the role of critical residues and interactions in the binding of pro-resolution and pro-inflammatory agonists.

Identification of novel brain penetrant GSK-3β inhibitors toward Alzheimer’s disease therapy by virtual screening, molecular docking, dynamic simulation, and MMPBSA analysis

One of the significant therapeutic targets for Alzheimer’s disease (AD) is Glycogen Synthase Kinase-3β (GSK-3β). Inhibition of GSK-3β can prevent hyperphosphorylation of tau, and thus prevent formation and accumulation of neurofibrillary tangles and neuropil threads that block intracellular transport, trigger unfolded protein response, and increase oxidative stress, cumulatively leading to neurodegeneration. In this study, we have performed structure-based virtual screening of two small-molecule libraries from ChemDiv CNS databases using AutoDock Vina to identify hit molecules based on their binding affinities compared to that of an established GSK-3β inhibitor, indirubin-3’-monoxime (IMO). Pharmacoinformatic screening on SwissADME and pkCSM servers enabled identification of lead molecules with favorable pharmacoinformatic properties for drug likeliness, including blood brain barrier (BBB) permeability. Further, molecular dynamic simulations identified six candidate lead molecules that show stable complex formation with GSK-3β in dynamic state under physiological conditions. Principal component analysis of the dynamic state was used to plot Free Energy Landscapes (FELs) of GSK-3β-ligand complexes. STRIDE secondary structure analysis of the lowest energy conformations identified from FEL plots, and binding free energy calculations by Molecular Mechanics Poisson-Boltzmann Surface Area ((ΔGbind )MM-PBSA) of the simulation trajectories led to the identification of two ligands as potential lead molecules having favorable free energy landscape profiles as well as significantly lower (ΔGbind )MM-PBSA in dynamic state compared to that of reference inhibitor IMO. Hence, this study identifies two novel brain penetrant GSK-3β inhibitors that are likely to have therapeutic potential against Alzheimer’s disease.

Integrated all-atom and coarse-grained simulations uncover structural, dynamics and energetic shifts in SARS-CoV-2 JN.1 and BA.2.86 variants

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the COVID-19 pandemic, is an enveloped, positive-stranded RNA virus that enters human cells by using its spike protein to bind to the human angiotensin-converting enzyme 2 (ACE2) receptor. Since its emergence, the virus has mutated, producing variants with increased transmissibility, immune evasion, and infectivity. The JN.1 variant, detected in January 2024, features a single substitution mutation (Leu455Ser) in the receptor-binding domain (RBD) of its spike protein, setting it apart from its parent lineage, BA.2.86. This variant has rapidly become globally predominant due to its enhanced transmission and significant epidemiological impact. To understand the causes behind the dominance of the JN.1 variant, we conducted a comprehensive study using all-atom molecular dynamics (MD) and coarse-grained MD simulations. This allowed us to examine the structural, dynamic, energetics and binding properties of the wild-type (Wuhan strain), BA.2.86, and JN.1 variants. Principal component and free energy landscape analyses revealed enhanced structural stability in the JN.1 variant. Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) assessments indicated lower binding affinity for JN.1 as compared to BA.2.86. Intermolecular interaction analyses further confirmed BA.2.86′s superior binding affinity over JN.1 and wild-type. Additionally, we compared and validated our findings against experimentally determined cryo-electron microscopy (cryo-EM) structures of JN.1 and BA.2.86 variants, confirming the reliability of our simulation results. Overall, this study provides crucial insights into the structural-dynamics-energetics features and physicochemical properties that have contributed to the global prevalence of the JN.1 variant and sheds light on its potential to generate future subvariants.

Enhancing Quality of Life in Multiple Sclerosis Patients Through Coadministration of FDA-Approved Immunomodulators and Melatonin

Objective: The primary goal of this study was to assess the binding characteristics and affinities of melatonin and certain U.S. Food and Drug Administration (FDA)-approved lipophilic drugs used in the treatment of multiple sclerosis (MS) with the brain and muscle Arnt-like 1 (BMAL1) clock protein. Additionally, the study aimed to investigate their potential as modulators of BMAL1 activity for therapeutic applications in MS.Methods: Molecular docking and simulation studies were conducted to investigate the interactions between the BMAL1 protein and the selected agents as ligands. Docking simulations were performed using AutoDock Vina, and key interactions were analyzed with Biovia Discovery Studio Visualizer. A molecular dynamics simulation was conducted using GROMACS 2020.4 and the binding free energies were calculated using the molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) method. The pharmacokinetic properties of the ligands were predicted using the BOILED-Egg model implemented in the SwissADME web tool.Results: Melatonin demonstrated the highest binding affinity (-8.5 kcal/mol) and most favorable binding free energy (-245.26±1.27 kJ/mol) with BMAL1, suggesting its potential synergistic activity with other FDA-approved drugs in MS therapy. The pharmacokinetic analysis indicated that all three ligands were likely to cross the blood-brain barrier and exhibit high gastrointestinal absorption, with teriflunomide and melatonin potentially achieving a better profile.Conclusion: This study highlights the potential of concomitant use of melatonin to modulate BMAL1 activity, providing a foundation for developing targeted chronotherapeutic strategies in MS treatment.

Evaluation of inhibition effect and interaction mechanism of antiviral drugs on main protease of novel coronavirus: Molecular docking and molecular dynamics studies

The outbreak of pneumonia caused by the novel coronavirus (SARS-CoV-2) has presented a challenge to public health. The identification and development of effective antiviral drugs is essential. The main protease (3CLpro) plays an important role in the viral replication of SARS-CoV-2 and is considered to be an effective therapeutic target. In this study, according to the principle of drug repurposing, a variety of antiviral drugs commonly used were studied by molecular docking and molecular dynamics (MD) simulations to obtain potential inhibitors of main proteases. 24 antiviral drugs were docked with 5 potential action sites of 3CLpro, and the drugs with high binding strength were further simulated by MD and the molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) binding free energy calculations. The results showed that the drugs with high flexibility could bind to 3CLpro better than those with low flexibility. The interaction mechanism between antiviral drugs and main protease was analyzed in detail by calculating the root mean square displacement (RMSD), root mean square fluctuation (RMSF) and interaction residues properties. The results showed that the six drugs with high flexibility (Remdesivir, Simnotrelvir, Sofosbuvir, Ledipasvir, Indinavir and Raltegravir) had strong binding strength with 3CLpro, and the last four antiviral drugs can be used as potential candidates for main protease inhibitors.

Discovering potential asthma therapeutics targeting hematopoietic prostaglandin D2 synthase: An integrated computational approach

Allergic asthma, a chronic inflammatory illness that affects millions worldwide, has serious economic and health consequences. Despite advances in therapy, contemporary treatments have poor efficacy and negative effects. This study investigates hematopoietic prostaglandin D2 synthase (HPGDS) as a potential target for novel asthma therapies. Targeting HPGDS may provide innovative treatment methods. A library of phytochemicals was used to find putative HPGDS inhibitors by structure-based and ligand-based virtual screening. Among the 2295 compounds screened, four compounds (ZINC208828240, ZINC95627530, ZINC14727536, and ZINC14711790) demonstrated strong binding affinities of −10.4, −10.3, −9.2, −9.1 kcal/mol respectively with key residues, suggesting their potential as a highly effective HPGDS inhibitor. Molecular dynamics (MD) simulations and Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) computations were further performed to evaluate the stability and binding affinity of the complexes. MD simulations and MMPBSA confirmed that compound ZINC14711790 showed high stability and binding affinity (binding energy −31.52 kcal/mol) than other compounds, including HQL-79, suggesting that this compound might be used as promising inhibitors to treat asthma. RMSD and RMSF analysis also revealed that ZINC14711790 exhibited strong dynamic stability. The findings of this study show the efficacy of ZINC14711790 as HPGDS inhibitors with high binding affinity, dynamic stability, and appropriate ADMET profile.

Computational exploration of compounds in Xylocarpus granatum as a potential inhibitor of Plasmodium berghei using docking, molecular dynamics, and DFT studies

Malaria remains a global health concern, with the emergence of resistance to the antimalarial drug atovaquone through cytochrome b (cyt b) being well-documented. This study was prompted by the presence of this mutation in cyt b to enable new drug candidates capable of overcoming drug resistance. Our objective was to identify potential drug candidates from compounds of Xylocarpus granatum by computationally assessing their interactions with Plasmodium berghei cyt b. Using computational methods, we modeled cyt b (GenBank: AF146076.1), identified the binding cavity, and analyzed the Ramachandran plot against cyt b. Additionally, we conducted drug-likeness and absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies, along with density functional theory (DFT) analysis of the compounds. Molecular docking and molecular dynamics simulation (MDS) were used to evaluate the binding energy and stability of the cyt b-ligand complex. Notably, our investigation highlighted kaempferol as a promising compound due to its high binding energy of 7.67 kcal/mol among all X. granatum compounds, coupled with favorable pharmacological properties (ADMET) and antiprotozoal properties at Pa 0.345 > Pi 0.009 (PASS value). DFT analysis showed that kaempferol has an energy gap of 4.514 eV. MDS indicated that all tested ligands caused changes in bonding and affected the structural conformation of cyt b, as observed before MDS (0 ns) and after MDS (100 ns). The most notable differences were observed in the types of hydrogen bonds between 0 and 100 ns. Nevertheles, MDS results from a 100 ns simulation revealed consistent behavior for kaempferol across various parameters including root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA), molecular mechanics-Poisson Boltzmann surface area (MM-PBSA), and hydrogen bonds. The cyt b-kaempferol complex demonstrated favorable energy stability, as supported by the internal energy distribution values observed in principal component analysis (PCA), which closely resembled those of the atovaquone control. Additionally, trajectory stability analysis indicated structural stability, with a cumulative eigenvalue of 24.7 %. Dynamic cross-correlation matrix (DCCM) analysis revealed a positive correlation among catalytic cytochrome residues within the amino acid residues range 119–268. The results of our research indicate that the structure of kaempferol holds promise as a potential candidate against Plasmodium.

Analysis of action of 1,4-naphthoquinone scaffold-derived compounds against acute myeloid leukemia based on network pharmacology, molecular docking and molecular dynamics simulation

1,4-Naphthoquinone scaffold-derived compounds has shown considerable pharmacological properties against cancer, including acute myeloid leukemia (AML) However, its impact and mechanisms in AML are uncertain. In this study, the mechanisms of 1,4-naphthoquinone scaffold-derived compounds against AML were investigated via network pharmacology, molecular docking and molecular dynamics simulation. ASINEX database was used to collect the 1,4-naphthoquinone scaffold-derived compounds, and compounds were extracted from the software to evaluate their drug similarity and toxicity. The potential targets of compounds were retrieved from the SwissTargetPrediction Database and the Similarity Ensemble Approach Database, while the potential targets of AML were obtained from the GeneCards databases and Gene Expression Omnibus. The STRING database was used to construct a protein–protein interaction (PPI) network, topologically and Cyto Hubb plugin of Cytoscape screen the central targets. After selecting the potential key targets, the gene ontology (GO) function annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed for the intersection targets, and a network map of “compounds-potential targets-pathway-disease” were constructed. Molecular docking of the compounds with the core target was performed, and core target with the strongest binding force and 1,4-naphthoquinone scaffold-derived compounds was selected for further molecular dynamics simulation and further molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) approach verification. In addition, the Bloodspot database was applied to perform the overall survival of core targets. A total of 19 1,4-naphthoquinone scaffold-derived compounds were chosen out, and then 836 targets of compounds, 96 intersection targets of AML were screened. Core targets include STAT3, TLR4, HSP90AA1, JUN, MMP9, PTPRC, JAK2, PTGS2, KIT and CSF1R. GO functional enrichment analysis revealed that 90 biological processes, 10 cell components and 12 molecular functions were enriched while KEGG pathway enrichment analysis revealed 34 enriched signaling pathways. Analysis of KEGG enrichment hinted that these 10 core genes were located in the pathways in cancer, suggesting that 1,4-naphthoquinone scaffold-derived compounds had potential activity against AML. Molecular docking analysis revealed that the binding energies between 1,4-naphthoquinone scaffold-derived compounds and the core proteins were all higher than − 6 kcal/mol, indicating that the 10 core targets all had strong binding ability with compounds. Moreover, a good binding capacity was inferred from molecular dynamics simulations between compound 7 and MMP9. The total binding free energy calculated using the MM/GBSA approach revealed values of − 6356.865 kcal/mol for the MMP9-7 complex. In addition, Bloodspot database results exhibited that HSP90AA1, MMP9 and PTPRC were associated with overall survival. The findings provide foundations for future studies into the interaction underlying the anti-AML potential of compounds with 1,4-naphthoquinone-based scaffold structures. Compounds with 1,4-naphthoquinone-based scaffold structures exhibits considerable potential in mitigating and treating AML through multiple targets and pathways.

Antimicrobial activity of compounds identified by artificial intelligence discovery engine targeting enzymes involved in Neisseria gonorrhoeae peptidoglycan metabolism

BackgroundNeisseria gonorrhoeae (Ng) causes the sexually transmitted disease gonorrhoea. There are no vaccines and infections are treated principally with antibiotics. However, gonococci rapidly develop resistance to every antibiotic class used and there is a need for developing new antimicrobial treatments. In this study we focused on two gonococcal enzymes as potential antimicrobial targets, namely the serine protease L,D-carboxypeptidase LdcA (NgO1274/NEIS1546) and the lytic transglycosylase LtgD (NgO0626/NEIS1212). To identify compounds that could interact with these enzymes as potential antimicrobials, we used the AtomNet virtual high-throughput screening technology. We then did a computational modelling study to examine the interactions of the most bioactive compounds with their target enzymes. The identified compounds were tested against gonococci to determine minimum inhibitory and bactericidal concentrations (MIC/MBC), specificity, and compound toxicity in vitro.ResultsAtomNet identified 74 compounds that could potentially interact with Ng-LdcA and 84 compounds that could potentially interact with Ng-LtgD. Through MIC and MBC assays, we selected the three best performing compounds for both enzymes. Compound 16 was the most active against Ng-LdcA, with a MIC50 value < 1.56 µM and MBC50/90 values between 0.195 and 0.39 µM. In general, the Ng-LdcA compounds showed higher activity than the compounds directed against Ng-LtgD, of which compound 45 had MIC50 values of 1.56–3.125 µM and MBC50/90 values between 3.125 and 6.25 µM. The compounds were specific for gonococci and did not kill other bacteria. They were also non-toxic for human conjunctival epithelial cells as judged by a resazurin assay. To support our biological data, in-depth computational modelling study detailed the interactions of the compounds with their target enzymes. Protein models were generated in silico and validated, the active binding sites and amino acids involved elucidated, and the interactions of the compounds interacting with the enzymes visualised through molecular docking and Molecular Dynamics Simulations for 50 ns and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA).ConclusionsWe have identified bioactive compounds that appear to target the N. gonorrhoeae LdcA and LtgD enzymes. By using a reductionist approach involving biological and computational data, we propose that compound Ng-LdcA-16 and Ng-LtgD-45 are promising anti-gonococcal compounds for further development.

Synthesis and Molecular Modeling Studies and In silico Anthelmintic Activity of N-(benzo[d]thiazol-2-yl)-3- Chloro-6-Nitrobenzo[b]thiophene- 2-Carboxamide Derivatives

Helminthiasis is a noteworthy health problem with increased morbidity. In this manuscript, we developed a series of N-(benzo[d]thiazol-2-yl)-3-chloro-6-nitrobenzo[b]thiophene-2-carboxamide derivatives (3a-f) and evaluated against Pheretima posthuma and Perionyx excavates helminths. The compounds 3a-f were synthesized by reaction of 3-chloro-6-nitrobenzo[b]thiophene-2-carbonyl chloride (1) and appropriate benzo[d]thiazol-2-amines (2a-f) presence of pyridine. A compound 1 was synthesized by reaction of 4-nitro-cinnamic acid reacts with thionyl chloride in the presence of pyridine and chlorobenzene. Results showed that molecule 3c observed with maximum anthelmintic against P. excavates and P. posthuma with mean paralyzing time of 13.15 min and 17.39 min and mean death time of 16.17 min and 20.14 min, respectively. Molecular docking against 3VRA receptor showed that molecule 3c showed maximum dock score of -7.3 kcal/mol and reference standard albendazole with dock score of -5.5 kcal/mol. Molecular dynamic simulation data reflected the stable ligand-receptor interaction. As per Molecular Mechanics Poisson-Boltzmann Surface Area analysis, maximum free binding energy of -31.224 kJ/mol showed by 3c and ARG 76 was the most contributed residue. Density functional theory calculation data confirmed that most of the molecules were soft molecules with electrophilic nature. Molecular electrostatic potential data of 3c showed that terminal nitro group, ketone group, -COO group of ester were responsible for electrophilic attack and benzo[b]thiophne and -NH groups were responsible for nucleophilic attack. The activity profile of the synthesized molecules against helminthes was 3c &amp;gt;3e &amp;gt;3d &amp;gt;3f &amp;gt;3b &amp;gt;3a.. KEYWORDS :Molecular docking, Molecular dynamic simulation, Molecular mechanics poisson-boltzmann surface area, Density functional theory, Anthelmintic activity.

Computational investigation of novel synthetic analogs of C-1′β substituted remdesivir against RNA-dependent RNA-polymerase of SARS-CoV-2

Remdesivir, a C-nucleotide prodrug binds to the viral RNA-dependent-RNA polymerase (RdRp) and inhibits the viral replication by terminating RNA transcription prematurely. It is reported in literature that interaction between the C-1’β–CN moiety of Remdesivir (RDV) and the Ser861 residue in RdRp enzyme, causes a delayed chain termination during the RNA replication process and is one of the important aspect of its mechanism of action. In the pursuance of increasing the biological activity of RDV and enhancing the SAR studies, against RNA viruses, we have designed its fourteen C1’β substituted analogs, 10 –23 bearing 4/5-membered heterocyclic rings. The docking and 100 ns molecular dynamics (MD) simulations of 10-23 to the RdRp protein (PDB ID: 7L1F) revealed important interactions between 2’,3’-diol, oxo group of phosphoramidate, nitrogen residues of heterocyclic rings of synthetic molecules with Arg555, Arg553, Ser759, Cys622, Asn691, Asp623 amino acid residues of protein. The docking score of 2-ethylbutyl ((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(1H-1,2,3-triazol-4-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate, 11 was found to be the higher than RDV among 14 new compounds i.e. -5.20 kcal/mol. Out of 3 compounds, 10, 12 and 13 submitted for MD simulations and Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) analysis, trifluoro-oxadiazole derivative, 13 showed higher binding energy as compared to Remdesivir. The predicted ADMET properties of 14 compounds showed their potential for being drug candidates. The present study suggests that substitution at the C1’β position by 4/5-membered rings plays an important role in the interactions between nucleoside/tide and target protein.