Dynamical Cross-correlation Matrix Research Articles

Generative adversarial network (GAN) model-based design of potent SARS-CoV-2 Mpro inhibitors using the electron density of ligands and 3D binding pockets: insights from molecular docking, dynamics simulation, and MM-GBSA analysis.

Deep learning-based generative adversarial network (GAN) frameworks have recently been developed to expedite the drug discovery process. These models generate novel molecules from scratch and validate them through molecular docking simulation to identify the most promising candidates for a given drug target. In this study, the SARS-CoV-2 main protease (Mpro) was selected as the drug target. Two distinct GAN algorithms were employed to generate novel small molecules. One approach utilized experimental electron density (ED-based) data of ligands for training to generate drug-like molecules, while the second approach leveraged the target binding pocket to capture spatial and bonding relationship between atoms within the binding pockets. The ED-based approach generated approximately 26,000 molecules, whereas the binding pocket-based method produced around 100 molecules. These generated molecules were subsequently ranked based on molecular docking results using the glide XP score (both flexible and rigid docking) and AutoDock Vina. To identify the most potent GAN-derived molecules, molecular docking was also performed on co-crystallized inhibitor molecules of Mpro. The six most promising molecules from these GAN approaches were further evaluated for stability, interactions, and MM-GBSA binding free energy through molecular dynamics simulations. This analysis led to the identification of four potent Mpro inhibitor molecules, all featuring a 2-benzyl-6-bromophenol scaffold. The binding free energies of these compounds were compared with those of other Mpro inhibitors, revealing that our compounds demonstrated better affinity for Mpro than some broad-spectrum protease inhibitors. The dynamic cross-correlation matrix plot indicated strongly correlated and anti-correlated regions, potentially linked to ligand binding.

Identification and interaction mechanism of novel small molecule antagonists targeting CC chemokine receptor 1/3/5 for treatment of non-small cell lung cancer.

Non-Small Cell Lung Cancer (NSCLC) was one of the most prevalent forms of lung cancer. Due to its ease of invasion and migration, the five-year survival rate was relatively low. Therefore, new strategies for NSCLC treatment were needed. CC chemokine receptor 1/3/5 (CCR1/CCR3/CCR5), a member of the G-protein coupled receptor family, could promote the migration and invasion of NSCLC cells by binding to related chemokines. Consequently, targeting CCR1, CCR3 and CCR5 might prevent the progression of the disease. So far, no compound had been reported as a common antagonist for CCR1, CCR3, and CCR5. In this research, we utilized virtual screening and structural optimization to obtain compound 5, which effectively inhibited the migration and invasion of NSCLC cells. Meanwhile, Western Blot and Enzyme linked immunosorbent assay (ELISA) manifested that compound 5 suppressed migration and invasion of NSCLC cells by suppressing the nuclear factor κB (NF-κB) and the consequently decreased Matrix Metalloproteinase-9(MMP-9) secretion. Moreover, drug affinity responsive target stability (DARTS) experiment and molecular simulations confirmed that compound 5 was capable of binding with CCR1/CCR3/CCR5, and Van der Waals forces were instrumental in the binding process. Ile91, Tyr113, Gln284, and Ser184(CCR1-ligand5), Ile189, Met213, and Leu209(CCR3-ligand5), Phe109, Gln194, and Thr195(CCR5-ligand5) had Van der Waals interactions with ligand 5. Dynamic cross-correlation matrix (DCCM) and free energy landscape (FEL) showed that compound 5 could stably bind to CCR1/CCR3/CCR5 to change conformation of the protein and the tendency of residue movements, leading to a persistent inhibitory effect. This study aimed to provide assistance in the rational design of common antagonists for CCR1, CCR3, and CCR5.

Identification of novel Influenza virus H3N2 nucleoprotein inhibitors using most promising synthetic Epicatechin derivatives

Influenza A virus is a leading cause of acute respiratory tract infections, posing a significant global health threat and resulting in substantial annual financial losses due to seasonal epidemics. Current treatment options are limited and increasingly ineffective due to viral mutations. This study aimed to identify potential drug candidates targeting the nucleoprotein of the H3N2 subtype of Influenza A virus. We focused on epicatechin derivatives and employed a suite of cheminformatics approaches, including ADMET profiling, drug-likeness evaluation, PASS predictions, molecular docking, molecular dynamics simulations, Principal Component Analysis (PCA), dynamic cross-correlation matrix (DCCM) analyses, and free energy landscape assessments. Molecular docking and dynamics simulations revealed strong and stable binding interactions between the derivatives and the target protein, with complexes 01 and 81 exhibiting the highest binding affinities. Additionally, ADMET profiling indicated favorable pharmacokinetic properties for these compounds, supporting their potential as effective antiviral agents. Compound 81 demonstrated exceptional quantum chemical descriptors, including a small HOMO-LUMO energy gap, high electronegativity, and significant softness, suggesting high chemical reactivity and strong electron-accepting capabilities. These properties enhance Compound 81’s potential to interact effectively with the H3N2 nucleoprotein. Experimental validation is strongly recommended to advance these compounds toward the development of novel antiviral therapies to address the global threat of influenza.

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.

In Silico Analysis of Conformational Dynamics and Energetic Landscapes of Putative Insulinase PF11_0189 From the Plasmodium falciparum Genome With Insulin‐Derived Peptides: Approach to Rationale Design of Insulin Peptide‐Based Inhibitors

ABSTRACTGlucose abnormality is one of the atypical symptoms mostly overlooked during severe malaria. Screening for proteases involved in glucose abnormality suggests a potential new drug target. PF11_0189 is a putative insulin degrading enzyme found in the genome of Plasmodium falciparum. In silico approach revealed that PF11_0189 is similar to the metalloproteases exhibiting a zinc binding motif. The substrate binding region of PF11_0189 catalytic domain is lined by residues of a mixed nature, enabling the accommodation of both hydrophobic and hydrophilic residues from substrates. Analysis of each amino acid position from combinatorial peptide library suggests Thr and Ser to be the most crucial residues as upon its mutation significant improvement is observed in the binding. The peptides P‐21 (VPICSLY), P‐70 (TMICVLY), and P‐121 (AVICSLY) demonstrate significantly better interaction within the active site than a template peptide (TSICSLY). Molecular dynamic simulations confirm the complex's integrity, with all structures within the qualitative limit of compactness and stability during the simulation time. Principal component analysis (PCA) reveals major conformational motions and different energy landscapes, while dynamic cross‐correlation matrix (DCCM) highlights residue interactions of the complexes. The insights obtained through computational methods provide clues about substrate selectivity in PF11_0189, which can be utilized for peptide‐based therapeutics against severe malaria.

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.

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.

Quercetin derivatives as potential inhibitors of Nipah virus phosphoprotein through in silico drug design approaches

The Nipah virus (NiV) is a pathogenic infection presenting a substantial risk to both human and animal communities. Despite its virulence, there are currently no available drugs or vaccines for NiV. To fight against this challenge, we applied a multi-step in silico drug design strategy, including PASS prediction, molecular docking, absorption, distribution, metabolism and excretion (ADMET) analysis, molecular dynamics simulations, frontier molecular orbitals calculations, dynamic cross-correlation matrix (DCCM), and principal component analysis (PCA). To find out the potential drug candidate against NiV target protein, more than 100 derivatives were taken from the PubChem database. After that, the Pa (probability “to be active"), and Pi (probability “to be inactive") calculation was conducted. Based on the maximum probability “to be active score (Pa), the top nine compounds were studied against NiV. Our findings suggest that the quercetin derivatives exhibit promising binding affinities with the Nipah virus phosphoprotein, particularly compounds 03 (−7.8 kcal/mol), 22 (−6.9 kcal/mol), and 89 (−7.3 kcal/mol). The molecular dynamics simulations over the 100 had confirmed excellent stability and ADMET profiles has reported that all the mentioned ligands are free from Hepatotoxicity, and AMES toxicity, suggesting them as promising candidates for anti-NiV drugs. Based on the results of molecular dynamics simulations, it was observed that the reported drug candidates 03, 22, and 89 exhibited a high degree of stability in forming protein-ligand complexes. These complexes showed only minor fluctuations in RMSF over the 100 ns simulation period. The utilization of frontier molecular orbitals aided in the understanding of the electronic structure behavior, providing strong evidence for their suitability. The study indicates that certain quercetin derivatives, such as 03, 22, and 89, show promise as potentially effective antiviral drug candidates against NiV. Future research should focus on experimental testing of these compounds to develop new antiviral drugs against NiV.

Investigating natural plant products as potential inhibitors to disrupt NS1 β-roll domain polymerisation in DENV2: a detailed computational chemistry approach

ABSTRACT The aim of this investigation is to design a novel drug, screened through various computational methods, that harnesses the historical evidence of plant products inhibiting viral infections. The beta-roll domain of Flavivirus NS1, crucial for its stability, membrane interaction and viral RNA replication, underscores its significance in disease pathogenesis, being the sole non-structural protein detected in the sera of DENV-infected patients. Our goal is to develop optimised compounds that disrupt NS1 β-roll domain polymerisation, mitigating hydrophobic core formation, to effectively inhibit DENV2 cytopathic infection by leveraging natural interference with viral replication. We created 10 plant-based ligand libraries and applied scaffold hopping and bioisosteric replacement to improve them. Computational methodologies, including virtual screening, molecular dynamics simulation, contact matrix and dynamic cross correlation matrix, were employed for analysing the dynamics of the protein with the association of ligand. ADMET analysis of ligand 126 revealed a favourable ADME profile with no observed toxicity properties. Calculations of pKd, pKi and pIC50 values indicated a heightened affinity of the ligand for the receptor protein, suggesting enhanced inhibitory action and a reduced dissociation rate. These encouraging findings suggest a greater potency of the drug, warranting further in vitro testing for validation.

Identification of Helicobacter pylori-carcinogenic TNF-alpha-inducing protein inhibitors via daidzein derivatives through computational approaches.

Gastric cancer is considered a class 1 carcinogen that is closely linked to infection with Helicobacter pylori (H. pylori), which affects over 1 million people each year. However, the major challenge to fight against H. pylori and its associated gastric cancer due to drug resistance. This research gap had led our research team to investigate a potential drug candidate targeting the Helicobacter pylori-carcinogenic TNF-alpha-inducing protein. In this study, a total of 45 daidzein derivatives were investigated and the best 10 molecules were comprehensively investigated using in silico approaches for drug development, namely pass prediction, quantum calculations, molecular docking, molecular dynamics simulations, Lipinski rule evaluation, and prediction of pharmacokinetics. The molecular docking study was performed to evaluate the binding affinity between the target protein and the ligands. In addition, the stability of ligand-protein complexes was investigated by molecular dynamics simulations. Various parameters were analysed, including root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius of gyration (Rg), hydrogen bond analysis, principal component analysis (PCA) and dynamic cross-correlation matrix (DCCM). The results has confirmed that the ligand-protein complex CID: 129661094 (07) and 129664277 (08) formed stable interactions with the target protein. It was also found that CID: 129661094 (07) has greater hydrogen bond occupancy and stability, while the ligand-protein complex CID 129664277 (08) has greater conformational flexibility. Principal component analysis revealed that the ligand-protein complex CID: 129661094 (07) is more compact and stable. Hydrogen bond analysis revealed favourable interactions with the reported amino acid residues. Overall, this study suggests that daidzein derivatives in particular show promise as potential inhibitors of H. pylori.

Insights into novel inhibitors intending HCMV protease a computational molecular modelling investigation for antiviral drug repurposing

Human cytomegalovirus (HCMV) is an important opportunistic pathogen that is the most significant viral cause of congenital birth abnormalities and is responsible for a high morbidity and death rate in immunocompromised patients. HCMV's rising severity and the limitations of current vaccines in preventing infection highlight the urgent need for effective antiviral drugs. This study aimed to identify small compounds using extensive & appropriate in-silico drug design techniques, including molecular docking, Post-docking MM-GBSA, ADMET, MD simulation, PCA, and DCCM were employed in this study capable of binding to the viral protease and inhibiting its activity, thereby preventing proteolytic processing during capsid maturation. 3516 compounds from life chemical were used in molecular docking, and the top four compounds having high binding affinity and promising ADMET properties with life chemicals ID: F3407-0101 (CID: 49667672), F6559-3323 (CID: 121022124), F6456-1266 (CID: 71810903), and F3411-7969 (CID: 50785034). MD simulation was also used to assess the stability of the protein-ligand complex structure. Finally, after MD simulation, principal component analysis (PCA), and dynamic cross-correlation matrix (DCCM) analysis were performed using trajectories, and we can suggest the best drug candidate which is CID: 50785034 (N-(3-fluoro-4-methylphenyl)-2-({7-oxo-8-[(oxolan-2-yl) methyl]-5-thia-1,8,10,11-tetraazatricyclo [7.3.0.0^ {2,6}] dodeca-2(6),3,9,11-tetraen-12-yl}sulfanyl)acetamide), another two compounds CID: 121022124, and CID: 71810903 which comes after CID: 50785034. All three compounds may have the potential to be developed as a therapy option for HCMV infection.

In silico computational prediction of Saussurea pulchella compounds with inhibitory effects on plasmepsin X in Plasmodiumfalciparum

Malaria poses serious problems in countries located in tropical and subtropical regions worldwide. Plasmodium falciparum is responsible for approximately 90 % of malaria-related deaths worldwide. Therefore, alternative treatments are required to effectively reduce the number of malaria cases. Therefore, the objective of this study was to explore alternative malaria treatments by identifying compounds targeting P. falciparum plasmepsin X and characterizing the interactions under various temperatures. Molecular docking was used to evaluate interactions between polyphenolic compounds from Saussurea pulchella and plasmepsin X, followed by stability analyses using molecular dynamics (MD) simulations. Selected compounds were analyzed for biological activity, reactivity, and toxicity. RMSD (root mean square deviation), RMSF (root mean square fluctuation), Rg (radius of gyration), SASA (solvent-accessible surface area), and H-bonds were evaluated. Furthermore, MM-PBSA (molecular mechanics Poisson–Boltzmann surface area), PCA (principal component analysis), and DCCM (dynamic cross-correlation matrix) were use to evaluate effects of various temperatures. Pinoresinol 4-glucoside had a binding energy of 10.006 kcal/mol and was predicted to be nontoxic. MD simulations of pinoresinol 4-glucoside were conducted at different temperatures (298 K, 300 K, 305 K, 310 K, and 320 K) over a trajectory of 150 ns, revealing a strong binding energy using the MM-PBSA method. Our findings suggest that pinoresinol 4-glucoside is an alternative treatment for malaria and should be further evaluated at the laboratory and clinical levels.

Investigation of the new substitution glycine to alanine within the Kringle-2 domain of reteplase: a molecular dynamics study.

Recombinant plasminogen activator (r-PA) consists of the Kringle-2 and protease domains of human tissue-type plasminogen. It is used clinically to treat coronary artery thrombosis and acute myocardial infarction. However, the expression and production of reteplase (r-PA) are limited due to its susceptibility to proteolysis during manufacturing processes. Therefore, efforts have been made to address this limitation. To enhance the conformational stability of r-PA and increase its resistance to proteolysis, we used Gly 6 Ala substitutions in the Kringle-2 domain through in silico . We created an in silico mutant collection with eight structures, incorporating four designated mutations (R103S, G39A, G53A, and G55A). Using MODELLER software and homology modeling, we developed three-dimensional structures for two Kringle-2 and tissue plasminogen activator protease domains, including the wild noncleavable form (R103S) and mutants with all four designated mutations. We assessed protein stability using a dynamic cross-correlation matrix by extracting global properties such as Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuation (RMSF) from trajectory files. The findings revealed that a single glycine-alanine substitution (G39A) enhanced the conformational stability of r-PA, as evidenced by improvements in RMSD, RMSF, radius of gyration, surface accessibility, hydrogen bond formation, eigenvector projection, and density analysis. The conformational stability of r-PA conferred by glycine replacement with alanine may decrease the propensity for proteolysis in protease - rich environments across various recombinant systems and potentially enhance its production and expression levels.

Comprehending conformational changes in EmrE, multidrug transporter at different pH: insights from molecular dynamics simulations

EmrE is a small multidrug resistance (SMR) pump of antiparallel topology that confers resistance to a broad range of polyaromatic cations in Escherichia coli. Atomic-level understanding of conformational changes for the selectivity of substrate and transport of a diverse array of drugs through the smallest known efflux pumps is crucial to multi-drug resistance. Therefore, the present study aims to provide insights into conformational changes during the transport through EmrE transporter at different pH. Molecular dynamics simulations have been carried out on the complete structure of EmrE in the absence of substrate. Computational analyses such as secondary structure, principal component, dynamic cross-correlation matrix, and hydrogen bond calculations have been performed. Analysis of MD trajectories in this study revealed pH-dependent interactions that influenced the structural dynamics of EmrE. Notably, at high pH, Glu14 and Tyr60 in both monomers formed electrostatic interactions, while these interactions decreased significantly at a low pH. Interestingly, a kink at helix 3 (H3) and dual open conformation of EmrE at low pH were also observed in contrast to a closed state discerned towards the periplasmic side at high pH. Significant interactions between C-terminal residues and residues at the edge of H1 & Loop1 and H3 & Loop3 were identified, suggesting their role in stabilizing the closed conformation of EmrE at the periplasmic end under high pH conditions. The present study enhances our understanding of EmrE’s conformational changes, shedding light on the pH-dependent mechanisms that are likely to impact its function in multi-drug resistance. Communicated by Ramaswamy H. Sarma