Dynamic Cross-correlation Research Articles

Identification of novel SARS-CoV-2 3CLpro inhibitors by molecular docking, in vitro assays, molecular dynamics simulations and DFT analyses.

SARS-CoV-2 pandemic has presented a significant threat to global health and the economy, necessitating urgent efforts to develop effective antiviral drugs. The main protease (3CLpro) of SARS-CoV-2 is a critical target for antiviral therapy due to its essential role in viral replication. In order to find new structural types of 3CLpro inhibitors to facilitate the solution to the problem of new virus resistance. Six potential pharmacologically bioactive compounds were identified by utilizing structure-based virtual screening and in vitro assays from the Topscience database containing 10 million compounds. Among these, compounds 34 and 36 exhibited potent inhibitory activity with IC50 values of 6.12 ± 0.42μM and 4.47 ± 0.39μM, respectively. To elucidate their binding mechanisms with 3CLpro, all-atom molecular dynamics (MD) simulations were conducted. Principal component analysis (PCA), free energy landscapes (FEL) and dynamic cross-correlation maps (DCCM) revealed that the binding of compounds 34 and 36 to 3CLpro significantly enhanced the structural stability of 3CLpro, reducing conformational flexibility and internal motions. The results of protein-ligand interaction showed that compounds 34 and 36 formed strong and stable interactions to key residues at active site of 3CLpro with different binding modes from S-217622. And HOMO-LUMO gap and molecular electrostatic potential distribution revealed the quantum chemical properties of compounds 34 and 36. These findings suggested that compounds 34 and 36 can be as novel SARS-CoV-2 3CLpro inhibitors and promising lead-like drug candidates for developing COVID-19 treatments.

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.

A dynamically consistent discretization method for the Goodwin model with nonlinear Phillips curve. Comparing qualitative and quantitative dynamics

AbstractThe Goodwin model is a widely used economic growth model able to explain endogenous fluctuations in employment rate and wage share; in its initial version, the standard Phillips curve is used. In the present work, we suggest a revised Phillips curve that takes into account how the wage share influences the rate of changes of the wage itself thus obtaining a continuous-time modified Goodwin model. Since applying models to real data often requires working in a discrete-time setup, we then move from the continuous-time to the discrete-time version of the proposed model, by using a general polynomial discretization method in backward and forward-looking (hybrid discretization). By comparing the continuous-time system to its discrete-time counterpart we prove that fixed points and local dynamics do not change, as long as the time step is not too high. Moreover, numerical simulations employing Dynamic Time Warping, cross-correlation, and semblance analysis consistently affirm that enhancing the similarity of quantitative dynamics is achieved by reducing the time step.

Global Dynamics of Environmental Kuznets Curve: A Cross-Correlation Analysis of Income and CO2 Emissions

The environmental Kuznets curve (EKC) hypothesis posits an inverted U-shaped relationship between economic growth and environmental degradation. However, there is no consensus regarding the EKC hypothesis among countries and regions of different income groups. This study revisits the EKC hypothesis by employing cross-correlation analysis to explore the income–CO2 emissions relationship across 158 countries and 44 regions from 1990 to 2020. The empirical method utilizes a dynamic cross-correlation coefficient (CCC) approach, allowing for the assessment of lead-lag dynamics between income and CO2 emissions over time. By categorizing nations into the World Bank’s income classifications, we found a heterogeneous EKC pattern highlighting distinct environmental–economic dynamics across different income groups. The findings indicate that high-income countries show a decoupling of economic growth from CO2 emissions; whereas, low-income countries still exhibit a positive correlation between both variables. This underscores the necessity for tailored policy interventions that promote carbon neutrality, while considering each country’s unique development stage. Our research contributes to the ongoing issue of sustainable economic development by providing empirical evidence of the different pathways nations follow in balancing growth with environmental preservation.

Inside-Out Rational Design of Ornithine Cyclodeaminase RlOCD from Rhizobium leguminosarum by a Multiregion Synergy Strategy for Efficient Synthesis of l-Pipecolic Acid.

Lysine cyclodeaminase (LCD)-mediated synthesis of l-pipecolic acid (l-PA) from l-lysine (l-Lys) is a promising approach. However, only one LCD has been reported, and its inadequate activity limits industrial applications. To address this problem, a substrate analogue-guided enzyme mining strategy was employed. A novel ornithine cyclodeaminase (OCD) from Rhizobium leguminosarum (RlOCD) was identified in combination with directed macrogenomic approaches. RlOCD displayed a conversion rate of 28% at a substrate loading as high as 1000 mM. A multiregion synergy strategy consisting of pocket reshaping, dynamical cross-correlation matrix-guided coevolutionary design, and surface modification was used to design RlOCD from the inside-out. A quadruple mutant (V93C/L119C/I170T/R90L) designated Mu4 with significantly increased activity was obtained, which showed a 28.46-fold increase in the catalytic efficiency. The conversion of Mu4 was 91% within 10 h at 1000 mM (146.19 g L-1) loading. The space-time yield of 282.1 g L-1 d-1 is the highest level ever reported. Molecular dynamics simulations and interaction analyses revealed that efficient pocket expansion and unique conformational rearrangements increased the affinity for the substrate, resulting in a more catalytically active conformation. This study expands the toolbox for the production of l-PA and demonstrates the effectiveness and potential of Mu4 for its production.

Exploration of phytoconstituents of Medhya Rasayana herbs to identify potential inhibitors for cerebroside sulfotransferase through high-throughput screening.

Cerebroside sulfotransferase (CST) is a key enzyme in sulfatide biosynthesis and regulation of the myelin sheath in the nervous system. To counter sulfatide accumulation with the deficiency of aryl sulfatase A, CST is considered a target protein in substrate reduction therapy in metachromatic leukodystrophy. In this study, 461 phytoconstituents from four herbs of Medhya Rasayana were screened using multi-pronged virtual screening methods including molecular docking, molecular dynamics (MD) simulation, and reverse pharmacophore analysis. The initial screening of the top 15 hits was based on the binding affinity of the compounds toward the CST substrate-binding site using the lowest free energy of a binding score cutoff of ≤ -7.5 kcal/mol, with the number of conformations in the largest cluster more than 75. The absorption, distribution, metabolism, and excretion (ADME) and toxicity-based pharmacokinetic analysis delivered the top four hits: 18alpha-glycyrrhetinic acid, lupeol, alpha carotene, and beta-carotene, with high blood-brain barrier permeability and negligible toxicity. Furthermore, a 100-ns simulation of protein-ligand complexes with a trajectory analysis of structural deviation, compactness, intramolecular interactions, principal component analysis, free energy landscape, and dynamic cross-correlation analysis showed the binding potential and positioning of the four hits in the binding pocket. Thus, an in-depth analysis of protein-ligand interactions from pre- and post-molecular dynamics simulation, along with reverse pharmacophore mapping, suggests that 18alpha-glycyrrhetinic acid is the most potent and specific CST inhibitor, while beta-carotene could be considered the second most potent compound for CST inhibition as it also exhibited overall stability throughout the simulation. Therefore, the computational drug screening approach applied in this study may contribute to the development of oral drugs as a therapeutic option for metachromatic leukodystrophy.

Phosphorylation at the D56 residue of MtrA in Mycobacterium tuberculosis enhances its DNA binding affinity by modulating inter-domain interaction

The response regulator, MtrA, plays a major role in adaptation to the host environment, cell division, replication, and dormancy activation of Mycobacterium tuberculosis (Mtb). The phosphorylation of the response regulator MtrA alters the downstream activity, typically involving changes in DNA binding activity. However, there is a substantial knowledge gap in understanding the phosphorylation-mediated structural changes in MtrA. Additionally, the active conformation of the protein has yet to be determined. Therefore, in this study, we have investigated the phosphorylation-induced conformational changes of MtrA using all-atom molecular dynamics simulations under various phosphorylation conditions. The results from this study demonstrate that the phosphorylation at D56 (pD56-MtrA) increases the compactness of the MtrA protein by stabilizing the inter-domain interaction between the regulatory domain and DNA binding domain. Notably, the higher occupancy H-bond (over 95 %) between Arg200-Asn100 in case of the pD56-MtrA condition, which is otherwise absent in the non-phosphorylated (uMtrA) condition, suggests the importance of this interaction in the active conformation of the protein. The dynamic cross-correlation analysis reveals that phosphorylation (especially pD56-MtrA) reduces the anti-correlated motions and increases correlated motions between different domains. Moreover, the higher DNA binding affinity of pD56-MtrA compared to uMtrA supported by molecular docking and MD simulation followed by MMPBSA analysis suggests that pD56-MtrA is the possible active conformation of the MtrA protein. Overall, this investigation elucidates the key structural changes in MtrA under different phosphorylated conditions, which might help in designing novel therapeutics against tuberculosis.

Promising Drug Delivery System for Cervical Cancer – A Future Approach

There is evidence that peptide targeting can be applied in cervical cancer therapy and for diagnosis involving the use of molecular imaging, hence developing peptide probes for this disease. Cervical cancer, which also has a high possibility of being prevented, is among the common tumors affecting women globally. Despite the occurrence being reduced greatly by screening, the illness remains fatal and its claims many lives annually, especially in the developing nations. In exercising such a perspective, specific public health efforts known to encourage physical activity, proper diet, and early detection of cervical cancer must begin to be taken seriously. When combined, doctors, health officers, and lawmakers could speed up the global deployment of such programs. California’s American Cancer Society, the present review enlists a host of pharmaceutical goods available in the market. This perspective of present-day research and manufacturing is devoted to the development of various types of nanocarriers for possible utilization in medication transport. Thus, overall cancer mortality appears to be not substantially different, though cancer incidence rates for both sexes are 50% lower in impoverished countries when compared to affluent nations. At the moment, there are new peptide probes that are developed solely for cervical cancer-perfectly suitable for targeting peptides applicable in therapeutic and diagnostic imaging. M13KE phage dodecapeptide (12-mer) peptide library was screened for recognition of human immunodeficiency virus type 1 (HIV-1) by immunofluorescence and flow cytometry; the S7 clone was identified as most suitable. A disease that affects many women is gynecologic health problems, and cervical cancer is the leading presenting complaint experienced regularly. Among these studies, QSAR, drug-likeness, PCA, dynamic cross-correlation matrix, molecular docking, molecular dynamics and quantum calculation properties can be listed. In the first literature survey, after identifying the potent antibacterial and anticancer activity of the molecule apigenin, some other promising derivatives were identified and more research has been carried out on them, focusing on their synthesized derivatives as inhibitors of DNA polymerase theta and cervical cancer caused by human papillomavirus. The results were streamlined by the use of in-silico molecular docking, which showed that all Apigenin derivatives and the targeted proteins had potential energy-binding relationships. Further validation is essential because this study used in-silico computational methodologies and produced excellent results. Applying in-silico molecular docking made the data more comprehensible, which showed the possible energy bindings of the targeted proteins and all the Apigenin variants. Due to the fact that this work utilized in-silico computational methods and obtained significant results, further validation is required. Hence, the present wet-lab experiments coupled with both in-vitro and in-vivo conditions, additional validation of the results.

Inhibitor binding and disruption of coupled motions in MmpL3 protein: Unraveling the mechanism of trehalose monomycolate transport.

Mycobacterial membrane protein Large 3 (MmpL3) of Mycobacterium tuberculosis (Mtb) is crucial for the translocation of trehalose monomycolate (TMM) across the inner bacterial cell membrane, making it a promising target for anti-tuberculosis (TB) drug development. While several structural, microbiological, and in vitro studies have provided significant insights, the precise mechanisms underlying TMM transport by MmpL3 and its inhibition remain incompletely understood at the atomic level. In this study, molecular dynamic (MD) simulations for the apo form and seven inhibitor-bound forms of Mtb MmpL3 were carried out to obtain a thorough comprehension of the protein's dynamics and function. MD simulations revealed that the seven inhibitors in this work stably bind to the central channel of the transmembrane domain and primarily forming hydrogen bonds with ASP251, ASP640, or both residues. Through dynamical cross-correlation matrix and principal component analysis analyses, several types of coupled motions between different domains were observed in the apo state, and distinct conformational states were identified using Markov state model analysis. These coupled motions and varied conformational states likely contribute to the transport of TMM. However, simulations of inhibitor-bound MmpL3 showed an enlargement of the proton channel, potentially disrupting coupled motions. This indicates that inhibitors may impair MmpL3's transport function by directly blocking the proton channel, thereby hindering coordinated domain movements and indirectly affecting TMM translocation.

Molecular hybridization assisted multi-technique approach for designing USP21 inhibitors to halt catalytic triad-mediated nucleophilic attack and suppress pancreatic ductal adenocarcinoma progression: A molecular dynamics study

AimsPancreatic cancer, the 12th-most common cancer, globally, is highly challenging to treat due to its complex epigenetic, metabolic, and genomic characteristics. In pancreatic ductal adenocarcinoma, USP21 acts as an oncogene by stabilizing the long isoform of Transcription Factor 7, thereby activating the Wnt signaling pathway. This study aims to inhibit activation of this pathway through computer-aided drug discovery. Accordingly, four libraries of compounds were designed to target the USP21's catalytic domain (Cys221, His518, Asp534), responsible for its deubiquitinating activity. Main methodsUtilizing an array of computer-aided drug design methodologies, such as molecular docking, virtual screening, principal component analysis, molecular dynamics simulation, and dynamic cross-correlation matrix, the structural and functional characteristics of the USP21-inhibitor complex were examined. Following the evaluation of the binding affinities, 20 potential ligands were selected, and the best ligand was subjected to additional molecular dynamics simulation study. Key findingsThe results indicated that the ligand-bound USP21 exhibited reduced structural fluctuations compared to the unbound form, as evident from RMSD, RMSF, Rg, and SASA graphs. ADMET analysis of the top ligand showed promising pharmacokinetic and pharmacodynamic profiles, good bioavailability, and low toxicity. The stable conformations of the proposed drug when bound to their target cavities indicate a robust binding affinity of −9.3 kcal/mol. The drug exhibits an elevated pKi value of 6.82, a noteworthy pIC50 value of 5.972, and a pKd value of 6.023 proving its high affinity and inhibitory potential towards the target. SignificanceIn-vitro testing of the top compound (MOLHYB-0436) could lead to its use as a potential treatment for pancreatic cancer.

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.

Substrate access tunnel engineering of a Fe-type nitrile hydratase from Pseudomonas fluorescens ZJUT001 for substrate preference adjustment and catalytic performance enhancement

Substrate access tunnel engineering is a useful strategy for enzyme modification. In this study, we improved the catalytic performance of Fe-type Nitrile hydratase (Fe-type NHase) from Pseudomonas fluorescens ZJUT001 (PfNHase) by mutating residue Q86 at the entrance of the substrate access tunnel. The catalytic activity of the mutant PfNHase-αQ86W towards benzonitrile, 2-cyanopyridine, 3-cyanopyridine, and 4-hydroxybenzonitrile was enhanced by 9.35-, 3.30-, 6.55-, and 2.71-fold, respectively, compared to that of the wild-type PfNHase (PfNHase-WT). In addition, the mutant PfNHase-αQ86W showed a catalytic efficiency (kcat/Km) towards benzonitrile 17.32-fold higher than the PfNHase-WT. Interestingly, the substrate preference of PfNHase-αQ86W shifted from aliphatic nitriles to aromatic nitrile substrates. Our analysis delved into the structural changes that led to this altered substrate preference, highlighting an expanded entrance tunnel region, theenlarged substrate-binding pocket, and the increased hydrophobic interactions between the substrate and enzyme. Molecular dynamic simulations and dynamic cross-correlation Matrix (DCCM) further supported these findings, providing a comprehensive explanation for the enhanced catalytic activity towards aromatic nitrile substrates.

Molecular insight into binding affinities and blockade effects of selected flavonoid compounds on the PD-1/PD-L1 pathway.

This study investigated the binding mechanisms of the flavonoids apigenin (Api), kaempferol (Kmp), and quercetin (Que) to the PD-L1 dimer using a combination of molecular modeling and experimental techniques. The binding free energy results demonstrated that the flavonoids could tightly bind to the PD-L1 dimer, with the binding abilities following the trend Que > Kmp > Api. Key residues Ile54, Tyr56, Met115, Ala121, and Tyr123 were identified as important for binding. The flavonoids primarily bind to the C-, F-, and G-sheet domains. The spontaneous formation of the complex systems was mainly driven by hydrophobic forces. Dynamic cross-correlation matrix and secondary structure analyses further indicated that the studied flavonoids could stably interact with the binding sites. ELISA results showed that the flavonoids could effectively block PD-1/PD-L1 interactions, although the inhibitory activity of Api was weaker. Therefore, flavonols might be more effective inhibitors compared to flavones. The findings of this study are expected to contribute to the development of novel flavonoids targeting the PD-1/PD-L1 pathway.

Insight into structural dynamics involved in activation mechanism of full length KRAS wild type and P-loop mutants

KRAS protein is known to be frequently mutated in various cancers. The most common mutations being at position 12, 13 and 61. The positions 12 and 13 form part of the phosphate binding region (P-loop) of KRAS. Owing to mutation, the protein remains in continuous active state and affects the normal cellular process. Understanding the structural changes owing to mutations in GDP-bound (inactive state) and GTP-bound (active state) may help in the design of better therapeutics. To understand the structural flexibility due to the mutations specifically located at P-loop regions (G12D, G12V and G13D), extensive molecular dynamics simulations (24 μs) have been carried for both inactive (GDP-bound) and active (GTP-bound) structures for the wild type and these mutants. The study revealed that the local structural changes at the site of mutations allosterically guide changes in distant regions of the protein through hydrogen bond and hydrophobic signalling network. The dynamic cross correlation analysis and the comparison of the correlated motions among different systems manifested that changes in SW-I, SW-II, α3 and the loop preceding α3 affects the interactions of GDP/GTP with different regions of the protein thereby affecting its hydrolysis. Further, the Markov state modelling analysis confirmed that the mutations, especially G13D imparts rigidity to structure compared to wild type and thus limiting its conformational state in either intermediate state or active state. The study suggests that along with SW-I and SW-II regions, the loop region preceding the α3 helix and α3 helix are also involved in affecting the hydrolysis of nucleotides and may be considered while designing therapeutics against KRAS.

In silico analysis of potential inhibitors for breast cancer targeting 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) catalyses.

Breast cancer (BC) is still one of the major issues in world health, especially for women, which necessitates innovative therapeutic strategies. In this study, we investigated the efficacy of retinoic acid derivatives as inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1), which plays a crucial role in the biosynthesis and metabolism of oestrogen and thereby influences the progression of BC and, the main objective of this investigation is to identify the possible drug candidate against BC through computational drug design approach including PASS prediction, molecular docking, ADMET profiling, molecular dynamics simulations (MD) and density functional theory (DFT) calculations. The result has reported that total eight derivatives with high binding affinity and promising pharmacokinetic properties among 115 derivatives. In particular, ligands 04 and 07 exhibited a higher binding affinity with values of -9.9 kcal/mol and -9.1 kcal/mol, respectively, than the standard drug epirubicin hydrochloride, which had a binding affinity of -8.2 kcal/mol. The stability of the ligand-protein complexes was further confirmed by MD simulations over a 100-ns trajectory, which included assessments of hydrogen bonds, root mean square deviation (RMSD), root mean square Fluctuation (RMSF), dynamic cross-correlation matric (DCCM) and principal component analysis. The study emphasizes the need for experimental validation to confirm the therapeutic utility of these compounds. This study enhances the computational search for new BC drugs and establishes a solid foundation for subsequent experimental and clinical research.

Measuring the dynamics of the stock market’s volume-price relationship: a new Hurst-based market-trend index

ABSTRACT Despite the rich literature on the relationship between trading volumes and stock prices, few studies explore the underlying linkage arising from multifractality. Here, we propose a Hurst-based market-trend index measuring the dynamic cross-correlation between volumes and prices, and illustrate its usefulness with applications on the Chinese stock market. We show that the new index can reflect the volume-price relationship’s underlying changes with varying market conditions across different sectors. We also show how the new index dominates the change in the Granger causality. Further economic analyses demonstrate how the new index can be used for improving trading strategies. The insights on the underlying relationship between stock volumes and prices are important for investment decisions and have insightful policy implications.

4D-QSAR, ADMET properties, and molecular dynamics simulations for designing N-substituted urea/thioureas as human glutaminyl cyclase inhibitors

Human glutaminyl cyclase (hQC) inhibitors have great potential to be used as anti- Alzheimer's disease (AD) agents by reducing the toxic pyroform of β-amyloid in the brains of AD patients. The four-dimensional quantitative structure activity relationship (4D-QSAR) model of N-substituted urea/thioureas was established with satisfying predictive ability and statistical reliability (Q2 = 0.521, R2 = 0.933, R2prep = 0.619). By utilizing the developed 4D-QSAR model, a set of new N-substituted urea/thioureas was designed and evaluated for their Absorption Distribution Metabolism Excretion and Toxicity (ADMET) properties. The results of molecular dynamics (MD) simulations, Principal component analysis (PCA), free energy landscape (FEL), dynamic cross-correlation matrix (DCCM) and molecular mechanics generalized Born Poisson-Boltzmann surface area (MM-PBSA) free energy calculations, revealed that the designed compounds were remained stable in protein binding pocket and compounds b ∼ f (−35.1 to −44.55 kcal/mol) showed higher binding free energy than that of compound 14 (−33.51 kcal/mol). The findings of this work will be a theoretical foundation for further research and experimental validation of urea/thiourea derivatives as hQC inhibitors.

Unveiling the potential of Traditional Chinese Medicines in combating NorA-mediated S. aureus drug resistance. A molecular dynamic study

Drug resistance Staphylococcus aureus (S. aureus) is emerging as the most prevalent pathogen in surgical wounds and orthopedic surgeries. NorA is a major drug efflux involved in the drug resistance, reducing intracellular drug concentrations. The current study aimed to find some potential inhibitors derived from Traditional Chinese Medicines (TCM) against NorA using a 500 ns molecular dynamics (MD) simulation. Root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), free energy, dynamic cross correlation matrix (DCCM) was computed. Three TCM compound; piperine, demethoxycurcumin, and tectorigenin exhibited many hydrogen bonds and hydrophobic contacts in the binding pockets residues, especially with ionizable residues (Arg 98, Glu 222, Asp 307, and Arg 310), forming two different charged regions. RMSD of NorA-piperine complex shows some initial instability at 5.2 Å, followed by an increase to 5.8 Å at 222 ns, and a further rise to 6.1 Å by the end of the 500 ns simulation period. Similarly, the NorA-demethoxycurcumin and NorA-tectorigenin complexes display elevated terminal RMSD of 7.9 Å each. RMSF, Rg, free energy, and binding pockets interactions confirmed the potential activity of piperine, demethoxycurcumin, and tectorigenin against NorA inhibition. In apo state NorA exhibited dispersion within the ranges of −100 to 150 (PC1: 39.97 %) while in complexed with ligands it illustrated significant differences in the motion patterns on PC1 (46.04 % and 27.39 %). The NorA-ligands DCCM displayed predominantly negatively correlated motions, particularly at the terminal resides from 200 to 370 where the pocket binding residues are located. These compounds also demonstrated drug-likeness and fitting best in the binding pocket residues (Asn > 137, Phe > 140, Phe > 303 Asp > 307, Arg > 310, Glu > 222, and Thr > 223). In conclusion, the compounds piperine, demethoxycurcumin, and tectorigenin interact with NorA through hydrogen bonds and hydrophobic contacts, particularly with key ionizable residues, Arg 98, Glu 222, Asp 307, and Arg 310, indicating potential inhibitory activity.

Elucidating the Molecular Basis of 14-3-3 Interaction with α-Synuclein: Insights from Molecular Dynamics Simulations and the Design of a Novel Protein-Protein Interaction Inhibitor.

Parkinson's disease is a widespread age-related neurodegenerative disorder characterized by the loss of dopaminergic neurons in the midbrain along with the appearance of protein aggregates, termed as "Lewy bodies" in the surviving neuronal cells. The components of Lewy bodies include proteins such as α-synuclein, 14-3-3, Parkin, and LRRK2, along with other cellular organelles, which, in their native state, perform a plethora of vital biological functions within the human biome. Formation of these aggregates renders these components inactive, thereby interfering with homeostasis. In this regard, the current study attempts to investigate the complexation behavior of all human-based 14-3-3 isoforms with α-synuclein via a combination of classical and enhanced sampling techniques and thereby determine the causality of these protein-protein interactions. The study indicated that upon complexation, the aggregation propensity of both 14-3-3 and α-synuclein increases, and this increment is propelled by the interfacial residues on either protein. Furthermore, mutagenesis studies revealed that Lys214 of 14-3-3 (henceforth termed K214A) is crucial for the formation of this binary complex. Principal component analysis combined with clustering studies unveiled the stability of these complexes in terms of their conformational distribution across the entire MD trajectory. For K214A, these clustered states were sparsely located, thereby making the transitions between them slightly difficult. Dynamic cross-correlation maps (DCCM) revealed the role of residues in the range 80-130 of 14-3-3 having a potential allosteric role in driving this complexation process. Finally, a novel peptide-based supramolecular inhibitor was designed, which exhibited higher proficiency in limiting the 14-3-3/α-synuclein interaction compared to the previous inhibitor model. It was also revealed that the presence of this inhibitor induces structural rigidity in α-synuclein, making changes in its conformations extremely difficult, as observed through Umbrella Sampling studies. Based on available information, the current study provides an insight into the molecular-level understanding of protein-protein interactions underlying Parkinson's disease and adds on to the methods of devising novel therapeutic approaches to treat the same.

Impact of Phosphorylation at Various Sites on the Active Pocket of Human Ferrochelatase: Insights from Molecular Dynamics Simulations.

Ferrochelatase (FECH) is the terminal enzyme in human heme biosynthesis, catalyzing the insertion of ferrous iron into protoporphyrin IX (PPIX) to form protoheme IX (Heme). Phosphorylation increases the activity of FECH, and it has been confirmed that the activity of FECH phosphorylated at T116 increases. However, it remains unclear whether the T116 site and other potential phosphorylation modification sites collaboratively regulate the activity of FECH. In this study, we identified a new phosphorylation site, T218, and explored the allosteric effects of unphosphorylated (UP), PT116, PT218, and PT116 + PT218 states on FECH in the presence and absence of substrates (PPIX and Heme) using molecular dynamics (MD) simulations. Binding free energies were evaluated with the MM/PBSA method. Our findings indicate that the PT116 + PT218 state exhibits the lowest binding free energy with PPIX, suggesting the strongest binding affinity. Additionally, this state showed a higher binding free energy with Heme compared to UP, which facilitates Heme release. Moreover, employing multiple analysis methods, including free energy landscape (FEL), principal component analysis (PCA), dynamic cross-correlation matrix (DCCM), and hydrogen bond interaction analysis, we demonstrated that phosphorylation significantly affects the dynamic behavior and binding patterns of substrates to FECH. Insights from this study provide valuable theoretical guidance for treating conditions related to disrupted heme metabolism, such as various porphyrias and iron-related disorders.