Dynamical Cross-correlation Matrix Research Articles

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.

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

Novel computational and drug design strategies for the inhibition of human T-cell leukemia virus 1-associated lymphoma by Astilbin derivatives

Human T-cell leukemia virus 1 (HTLV-1) associated lymphoma is a devastating malignancy triggered by HTLV-1 infections. We employeda comprehensive drug design and computational strategy in this work to explore the inhibitory activitiesof Astilbin derivatives against HTLV-1-associated lymphoma. We evaluated the stability, binding affinities, and various computational analysis of Astilbin derivatives against target proteins, such as HTLV-1 main protease and HTLV-1 capsid protein. The root mean square deviation (RMSD), root mean square fluctuation, radius of gyration, hydrogen bond analysis, principal component analysis (PCA) and dynamic cross-correlation matrix (DCCM) were applied to characterize these protein–ligand interactions further. Ligand-03 and ligand-04 exhibited notable binding affinity to HTLV-1 capsid protein, while ligand-05 displayed high binding affinity to HTLV-1 protease. MD simulation analysis revealed that ligand-03, bound to HTLV-1 capsid protein, demonstrated enhanced stability with lower RMSD values and fewer conformational changes, suggesting a promising binding orientation. Ligand-04, despite stable binding, exhibited increased structural deviations, making it less suitable. Ligand-05 demonstrated stable binding to HTLV-1 protease throughout the simulation period at 100 nanoseconds. Hydrogen bond analysis indicated that ligand-05 formed persistent hydrogen bonds with significantresidues, contributing to its stability. PCA highlighted ligand-03's more remarkable conformational changes, while DCCM showed ligand-05's distinct dynamics, indicating its different behavior in the complex. Furthermore, binding free energy calculations supported the favorable interactions of ligand-03 and ligand-04 with HTLV-1 capsid protein, while ligand-05 showed weaker interactions with HTLV-1 protease. Molecular electrostatic potential and frontier molecular orbital analyses provided insights into these compounds’ charge distribution and stability. In conclusion, this research found Astilbin derivatives as potential inhibitors of HTLV-1-associated lymphoma. Future attempts at drug development will benefit from the steady interaction landscape provided by Ligand-03, Ligand-04 and Ligand-05, which showed the most attractive binding profile with the target protein. These results open up new opportunities for innovative drug development, and more experimental testing should be done between Astilbin derivatives and HTLV-1-associated lymphoma. Communicated by Ramaswamy H. Sarma

Structure-oriented engineering of nitrile hydratase: Reshaping of substrate access tunnel and binding pocket for efficient synthesis of cinnamamide

Cinnamamide and its derivatives are the most common and important building blocks widely present in natural products. Currently, nitrile hydratase (NHase, EC 4.2.1.84) has been widely used in large-scale industrial production of nicotinamide and acrylamide, while its catalytic activity is extremely low or inactive for bulky nitrile substrates such as cinnamonitrile. Therefore, beneficial variant βF37P/L48P/F51N were obtained from PtNHase of Pseudonocardia thermophila JCM3095 by reshaping of substrate access tunnel and binding pocket, which exhibited 14.88-fold improved catalytic efficiency compared to the wild-type PtNHase. Structure analysis, molecular dynamics simulations and dynamical cross-correlation matrix (DCCM) analysis revealed that the introduced mutations enlarged the substrate access tunnel and binding pocket, enhanced overall anti-correlated movements of enzymes, which would promote product release during the dynamic process of catalysis. In a hydration process, the complete conversion of 5 mM cinnamonitrile was achieved by βF37P/L48P/F51N in a 50 mL reaction, with cinnamamide yield of almost 100 % and productivity of 0.736 g L−1 h−1. The study demonstrates the co-evolution of substrate access tunnel and binding pocket is an effective strategy, and provides a valuable reference for future research. Furthermore, NHases have huge potential for catalyzing bulky nitriles to form corresponding amides in large-scale industrial production.

Computational screening of potential bromodomain-containing protein 2 inhibitors for blocking SARS-CoV-2 infection through pharmacophore modeling, molecular docking and molecular dynamics simulation

Recently, human bromodomain-containing protein 2 (BRD2) has been reported as a potential drug target in host cells to combat SARS-CoV-2 as well as to treat COVID-19. In this study, we aimed to screen potential BRD2 inhibitors as anti- SARS-CoV-2 agents through computational approach. A pharmacophore model was generated with crystal structure of BRD2 in complex with RVX208 using ZINCPharmer server, and 10,842 compounds were screened from ZINC15 database against the pharmacophore model. Next, 102 compounds exhibited more affinity to BRD2 than control compound (RVX208) were screened using molecular docking. The top five hits (ZINC20417563, ZINC12322175, ZINC12391479, ZINC13098192, and ZINC20407881), which showed docking affinity to BRD2 with −10, −9.9, −9.8, −9.7 and −9.7 kcal/mol, respectively, were subjected to 100 ns molecular dynamics simulation to evaluate the stability of docked complexes and their interaction mechanisms. The appropriate stability of these complexes was displayed, and these compounds were found to be closely adhered to the binding site of the BRD2 protein based on the global dynamics analysis with RMSD, RMSF, Rg, SASA, DSSP and H-bond. The essential dynamics analysis with principal component analysis, dynamic cross-correlation matrix, and free energy landscape showed BRD2 binding of the screened compounds remained the stable conformation throughout molecular dynamics simulation. In addition, the pharmacokinetic and ADMET properties of the five compounds showed these compounds could be potential drug candidates. The findings of this study may contribute to further examinational validation and rational design of novel BRD2 inhibitors as anti-SARS-CoV-2 agents.

Polyphenolic flavonoid compounds act as the inhibitory potential of aggregation process: Implications for the prevention and therapeutics against FALS-associated D101G SOD1 mutant

Aggregation of proteins is a biological phenomenon caused by misfolded proteins. Human superoxide dismutase (hSOD1) misfolding and aggregation underlie the neurological illness amyotrophic lateral sclerosis (ALS). The most significant contributing factor to ALS is genetic point mutations in SOD1. particularly, D101G mutant is the most harmful because it significantly reduces the life expectancy of patients. Subsequently, the use of natural polyphenolic flavonoids is strongly recommended to reduce the amyloidogenic behavior of protopathic proteins. In this study, using computational parameters such as protein-ligand interaction and molecular dynamics (MD) simulation analyses, we are trying to identify a pharmacodynamically promising flavonoid compound that can effectively inhibit the pathogenic behavior of the D101G mutant. Epigallocatechin-gallate (EGCG), Hesperidin, Isorhamnetin, and Diosmetin were identified as potential leads in a preliminary screening of flavonoids to anti-amyloid action. The results of MD showed that the binding of flavonoids to D101G mutant caused changes in stability, hydrophobicity of protein, and flexibility, as well as significantly led to the restoration of lost hydrogen bonds. Secondary structure analysis showed that protein destabilization and the increased propensity of β-sheet caused by the mutation were restored to the wild-type state upon binding of flavonoids. Besides, to differentiate aggregation, we elucidated alterations in the free energy landscape (FEL) and dynamic cross-correlation matrix (DCCM) of WT-SOD1 and mutant (unbound /bound) states. Among flavonoids, Epigallocatechin-gallate and Hesperidin had the most therapeutic efficacy against the D101G mutant. Therefore, Epigallocatechin-gallate and Hesperidin promise considerable therapeutic potential to develop highly effective inhibitors in reducing fatal and irreversible ALS.

Novel computational and drug design strategies for inhibition of human papillomavirus-associated cervical cancer and DNA polymerase theta receptor by Apigenin derivatives

The present study deals with the advanced in-silico analyses of several Apigenin derivatives to explore human papillomavirus-associated cervical cancer and DNA polymerase theta inhibitor properties by molecular docking, molecular dynamics, QSAR, drug-likeness, PCA, a dynamic cross-correlation matrix and quantum calculation properties. The initial literature study revealed the potent antimicrobial and anticancer properties of Apigenin, prompting the selection of its potential derivatives to investigate their abilities as inhibitors of human papillomavirus-associated cervical cancer and DNA polymerase theta. In silico molecular docking was employed to streamline the findings, revealing promising energy-binding interactions between all Apigenin derivatives and the targeted proteins. Notably, Apigenin 4′-O-Rhamnoside and Apigenin-4′-Alpha-l-Rhamnoside demonstrated higher potency against the HPV45 oncoprotein E7 (PDB ID 2EWL), while Apigenin and Apigenin 5-O-Beta-d-Glucopyranoside exhibited significant binding energy against the L1 protein in humans. Similarly, a binding affinity range of − 7.5 kcal/mol to − 8.8 kcal/mol was achieved against DNA polymerase theta, indicating the potential of Apigenin derivatives to inhibit this enzyme (PDB ID 8E23). This finding was further validated through molecular dynamic simulation for 100 ns, analyzing parameters such as RMSD, RMSF, SASA, H-bond, and RoG profiles. The results demonstrated the stability of the selected compounds during the simulation. After passing the stability testing, the compounds underwent screening for ADMET, pharmacokinetics, and drug-likeness properties, fulfilling all the necessary criteria. QSAR, PCA, dynamic cross-correlation matrix, and quantum calculations were conducted, yielding satisfactory outcomes. Since this study utilized in silico computational approaches and obtained outstanding results, further validation is crucial. Therefore, additional wet-lab experiments should be conducted under in vivo and in vitro conditions to confirm the findings.

Identification of PPA1 inhibitor candidates for potential repurposing in cancer medicine.

Inorganic pyrophosphatase 1 (PPA1) is pivotal to cellular metabolism as it facilitates the hydrolysis of PPi-a by-product of various metabolic processes that influence cell growth and differentiation. Overexpression of PPA1 enzyme has been linked to diminished patient survival and was shown to influence tumor cell dynamics, thereby positioning it as a potential therapy target for a variety of cancers including colorectal cancer, diffuse large B-cell lymphoma, and lung adenocarcinoma. Despite this therapeutic promise, there are no known inhibitors of PPA1 as of today. In this study, we searched for potential PPA1 inhibitors using a molecular docking screen of 30 470 compounds with a history of clinical trials and/or US Food and Drug Administration approval. We specifically targeted the active pocket that coincides with the established catalytic domain. Our screen identified promising hits, which we further subjected to ADMET (absorption, distribution, metabolism, excretion, and toxicity) filtering. Subsequent molecular dynamics (MD) analyses were conducted on devazepide, quinotolast, and tarazepide-the three substances that successfully navigated all filters. MD analyses reinforced the stability of the protein-ligand complexes and confirmed ligand binding, as substantiated by our root mean square deviation, radius of gyration and secondary structures of proteins analyses. Furthermore, Molecular Mechanics Poisson-Boltzmann Surface Area calculations post-MD identified devazepide and quinotolast as showing higher binding affinities; being supported by principal component analysis, free energy landscape, and dynamic cross-correlation matrix results. Overall, our study reveals devazepide and quinotolast as potential candidates for PPA1 inhibition which could be considered for repurposing studies that need further experimental validation. These results not only reveal a potential for clinical repurposing for PPA1 inhibition but they also offer valuable insights into the development of future compounds for targeting the crucial PPA1 enzyme.

In vitro and in silico analysis of Solanum torvum fruit and methyl caffeate interaction with cholinesterases

Oxidative stress along with dysfunction in cholinergic neurotransmission primarily underlies cognitive impairment. A significant approach to mitigate cognitive dysfunction involves the inhibition of cholinesterases, namely acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Exploring the potential antioxidant and anticholinesterase effects of edible plants holds promise for their utilization as botanicals to enhance cognition. Solanum torvum fruit with vast biological properties are used as food. In the present study, butanolic extract of S. torvum fruits (BESTF) was prepared. Additionally, the study investigated into the properties of methyl caffeate (MC), a compound present in S. torvum, obtained in its pure form. In vitro antioxidant and anticholinesterases activity of BESTF and MC were determined. BESTF and MC showed potent antioxidant property. BESTF and MC dose-dependently inhibited AChE (IC50 values: 166.6 µg/ml and 680.6 µM, respectively) and BChE (IC50 values: 161.55 µg/ml and 413 µM, respectively). BESTF and MC inhibited AChE and BChE in competitive mode. Active site gorge of AChE/BChE was occupied by MC which formed interaction with amino acids present in catalytic site and PAS in in silico. Further, molecular dynamics simulations followed by free energy calculation, principal component analysis and dynamic cross-correlation matrix provided the compelling evidence that that MC maintained stable interactions during MD simulation with AChE and BChE. Collectively, the results from the present study underlines the cognitive-enhancing effect of BESTF and MC.

Antimalarial drug discovery against malaria parasites through haplopine modification: An advanced computational approach.

The widespread emergence of antimalarial drug resistance has created a major threat to public health. Malaria is a life-threatening infectious disease caused by Plasmodium spp., which includes Apicoplast DNA polymerase and Plasmodium falciparum cysteine protease falcipain-2. These components play a critical role in their life cycle and metabolic pathway, and are involved in the breakdown of erythrocyte hemoglobin in the host, making them promising targets for anti-malarial drug design. Our current study has been designed to explore the potential inhibitors from haplopinederivatives against these two targets using an in silico approach. A total of nine haplopine derivatives were used to perform molecular docking, and the results revealed that Ligands 03 and 05 showed strong binding affinity compared to the control compound atovaquone. Furthermore, these ligand-protein complexes underwent molecular dynamics simulations, and the results demonstrated that the complexes maintained strong stability in terms of RMSD (root mean square deviation), RMSF (root mean square fluctuation), and Rg (radius of gyration) over a 100 ns simulation period. Additionally, PCA (principal component analysis) analysis and the dynamic cross-correlation matrix showed positive outcomes for the protein-ligand complexes. Moreover, the compounds exhibited no violations of the Lipinski rule, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) predictions yielded positive results without indicating any toxicity. Finally, density functional theory (DFT) and molecular electrostatic potential calculations were conducted, revealing that the mentioned derivatives exhibited better stability and outstanding performance. Overall, this computational approach suggests that these haplopine derivatives could serve as a potential source for developing new, effective antimalarial drugs to combat malaria. However, further in vitro or in vivo studies might be conducted to determine their actual effectiveness.

An in-silico receptor-pharmacophore based multistep molecular docking and simulation study to evaluate the inhibitory potentials against NS1 of DENV-2

DENV-2 strain is the most fatal and infectious of the five dengue virus serotypes. The non-structural protein NS1 encoded by its genome is the most significant protein required for viral pathogenesis and replication inside the host body. Thus, targeting the NS1 protein and designing an inhibitor to limit its stability and secretion is a propitious attempt in our fight against dengue. Four novel inhibitors are designed to target the conserved cysteine residues (C55, C313, C316, and C329) and glycosylation sites (N130 and N207) of the NS1 protein in an attempt to halt the spread of the dengue infection in the host body altogether. Numerous computer-aided drug designing techniques including molecular docking, molecular dynamics simulation, virtual screening, principal component analysis, and dynamic cross-correlation matrix were employed to determine the structural and functional activity of the NS1-inhibitor complexes. From our analysis, it was evident that the extent of structural and atomic level fluctuations of the ligand-bound protein exhibited a declining trend in contrast to unbound protein which was prominently noticeable through the RMSD, RMSF, Rg , and SASA graphs. The ADMET analysis of the four ligands revealed a promising pharmacokinetics and pharmacodynamic profile, along with good bioavailability and toxicity properties. The proposed drugs when bound to the targeted cavities resulted in stable conformations in comparison to their unbound state, implying they have good affinity promising effective drug action. Thus, they can be tested in vitro and used as potential anti-dengue drugs. Communicated by Ramaswamy H. Sarma

Target specific inhibition of West Nile virus envelope glycoprotein and methyltransferase using phytocompounds: an in silico strategy leveraging molecular docking and dynamics simulation.

Mosquitoes are the primary vector for West Nile virus, a flavivirus. The virus's ability to infiltrate and establish itself in increasing numbers of nations has made it a persistent threat to public health worldwide. Despite the widespread occurrence of this potentially fatal disease, no effective treatment options are currently on the market. As a result, there is an immediate need for the research and development of novel pharmaceuticals. To begin, molecular docking was performed on two possible West Nile virus target proteins using a panel of twelve natural chemicals, including Apigenin, Resveratrol, Hesperetin, Fungisterol, Lucidone, Ganoderic acid, Curcumin, Kaempferol, Cholic acid, Chlorogenic acid, Pinocembrin, and Sanguinarine. West Nile virus methyltransferase (PDB ID: 2OY0) binding affinities varied from -7.4 to -8.3 kcal/mol, whereas West Nile virus envelope glycoprotein affinities ranged from -6.2 to -8.1 kcal/mol (PDB ID: 2I69). Second, substances with larger molecular weights are less likely to be unhappy with the Lipinski rule. Hence, additional research was carried out without regard to molecular weight. In addition, compounds 01, 02, 03, 05, 06, 07, 08, 09, 10 and 11 are more soluble in water than compound 04 is. Besides, based on maximum binding affinity, best three compounds (Apigenin, Curcumin, and Ganoderic Acid) has been carried out molecular dynamic simulation (MDs) at 100 ns to determine their stability. The MDs data is also reported that these mentioned molecules are highly stable. Finally, advanced principal component analysis (PCA), dynamics cross-correlation matrices (DCCM) analysis, binding free energy and dynamic cross correlation matrix (DCCM) theoretical study is also included to established mentioned phytochemical as a potential drug candidate. Research has indicated that the aforementioned natural substances may be an effective tool in the battle against the dangerous West Nile virus. This study aims to locate a bioactive natural component that might be used as a pharmaceutical.

Binding Mechanism of CD47 with SIRPα Variants and Its Antibody: Elucidated by Molecular Dynamics Simulations.

The intricate complex system of the differentiation 47 (CD47) and the signal-regulatory protein alpha (SIRPα) cluster is a crucial target for cancer immunotherapy. Although the conformational state of the CD47-SIRPα complex has been revealed through crystallographic studies, further characterization is needed to fully understand the binding mechanism and to identify the hot spot residues involved. In this study, molecular dynamics (MD) simulations were carried out for the complexes of CD47 with two SIRPα variants (SIRPαv1, SIRPαv2) and the commercially available anti-CD47 monoclonal antibody (B6H12.2). The calculated binding free energy of CD47-B6H12.2 is lower than that of CD47-SIRPαv1 and CD47-SIRPαv2 in all the three simulations, indicating that CD47-B6H12.2 has a higher binding affinity than the other two complexes. Moreover, the dynamical cross-correlation matrix reveals that the CD47 protein shows more correlated motions when it binds to B6H12.2. Significant effects were observed in the energy and structural analyses of the residues (Glu35, Tyr37, Leu101, Thr102, Arg103) in the C strand and FG region of CD47 when it binds to the SIRPα variants. The critical residues (Leu30, Val33, Gln52, Lys53, Thr67, Arg69, Arg95, and Lys96) were identified in SIRPαv1 and SIRPαv2, which surround the distinctive groove regions formed by the B2C, C'D, DE, and FG loops. Moreover, the crucial groove structures of the SIRPα variants shape into obvious druggable sites. The C'D loops on the binding interfaces undergo notable dynamical changes throughout the simulation. For B6H12.2, the residues Tyr32LC, His92LC, Arg96LC, Tyr32HC, Thr52HC, Ser53HC, Ala101HC, and Gly102HC in its initial half of the light and heavy chains exhibit obvious energetic and structural impacts upon binding with CD47. The elucidation of the binding mechanism of SIRPαv1, SIRPαv2, and B6H12.2 with CD47 could provide novel perspectives for the development of inhibitors targeting CD47-SIRPα.

Computational insights into the binding of pimodivir to the mutated PB2 subunit of the influenza A virus

ABSTRACT Influenza A virus (IAV) is reported to develop Pimodivir resistance because of multiple mutations within the Polymerase basic 2 protein (PB2) of IAV. The lack of a high-resolution structure of these PB2 mutants complexed with Pimodivir hinders efforts to understand the drug resistance. Here we decipher the binding differences of Pimodivir in the wild-type and mutant systems Q306H, S324I, S324N, S324R, F404Y, and N510 T of IVA PB2 using homology modelling, molecular dynamics, molecular docking, and density functional theory simulations. The key residues responsible for Pimodivir binding were identified as Glu361, Arg355, Arg332, His357, and Phe323. Those mutations, mainly N510 T, result in significant conformational changes of Pimodivir in the PB2 active site. As a result, the affinity of Pimodivir is significantly reduced in the N510 T system. The mutation effects are less pronounced in the other mutant systems. Dynamic cross-correlation matrix (DCCM) analyses suggest that the single-point mutation N510 T produces an allosteric effect on the ligand-binding domain, thus reducing ligand-binding affinity. The present study reveals how a single-point mutation modulates the Pimodivir binding in IAV PB2, which provides important insights into designing new Pimodivir analogues with better binding affinities.

Computational pharmacology profiling of borapetoside C against melanoma

Melanoma,also known as a ‘black tumor’, begins in the melanocytes when cells (that produce pigment) grows out of control. Immunological dysregulation, which raises the risk for multiple illnesses, including melanoma, may be influenced by stress tiggered through viral infection, long term effects of ultraviolet radiation, environmental pollutants etc. Borapetoside C is one of the phytoconstituents from Tinospora crispa, and its biological source has been reported for its antistress property. Network pharmacology and KEGG pathway analysis of borapetoside C-regulated proteins were conducted to identify the hub genes involved in melanoma development. Further, a molecular docking was performed between borapetoside C and targets involved in melanoma. Further, the top 3 complexes were selected based on the binding energy to conduct molecular dynamics simulations to evaluate the stability of ligand-protein complex followed by principal component analysis and dynamic cross-correlation matrix. In addition, borapetoside C was also screened for its pharmacokinetics and toxicity profile. Network Pharmacology studies and KEGG pathway analysis revealed 8 targets involved in melanoma. Molecular docking between borapetoside C and targets involved in melanoma identified 3 complexes with minimum binding i.e. borapetoside C- MAP2K1, MMP9, and EGFR. Further, molecular dynamics simulations showed a stable complex of borapetoside C with MMP9 and EGFR. The present study suggested that borapetoside C may target MMP9 and EGFR to possess an anti-melanoma property. This finding can be useful in developing a novel therapeutic agent against melanoma from a natural source. Communicated by Ramaswamy H. Sarma

Discovering potential inhibitors of Raf proto-oncogene serine/threonine kinase 1: a virtual screening approach towards anticancer drug development

Raf proto-oncogene serine/threonine kinase 1 (RAF1 or c-Raf) is a serine/threonine protein kinase crucial in regulating cell growth, differentiation, and survival. Any disruption or overexpression of RAF1 can result in neoplastic transformation and other disorders such as cardiomyopathy, Noonan syndrome, leopard syndrome, etc. RAF1 has been identified as a potential therapeutic target in drug development against various complex diseases, including cancer, due to its remarkable role in disease progression. Here, we carried out a multitier virtual screening study involving different in-silico approaches to discover potential inhibitors of RAF1. After applying the Lipinski rule of five, we retrieved all phytocompounds from the IMPPAT database based on their physicochemical properties. We performed a molecular docking-based virtual screening and got top hits with the best binding affinity and ligand efficiency. Then we screened out the selected hits using the PAINS filter, ADMET properties, and other druglike features. Eventually, PASS evaluation identifies two phytocompounds, Moracin C and Tectochrysin, with appreciable anti-cancerous properties. Finally, all-atom molecular dynamics simulation (MDS) followed by interaction analysis was performed on the elucidated compounds in complex with RAF1 for 200 ns to investigate their time-evolution dynamics and interaction mechanism. Molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) and Dynamical Cross-Correlation Matrix (DCCM) analyses then followed these results from the simulated trajectories. According to the results, the elucidated compounds stabilize the RAF1 structure and lead to fewer conformational alterations. The results of the current study indicated that Moracin C and Tectochrysin could serve as potential inhibitors of RAF1 after required validation. Communicated by Ramaswamy H. Sarma

Binding affinity and conformational change predictions for a series of inhibitors with RuBisCO in a carbon dioxide gas and water environment by multiple computational methods

Ribulose 1, 5-bisphosphate carboxylase-oxygenase (RuBisCO), a Calvin cycle enzyme, is responsible for absorbing the majority of atmospheric CO2 into photosynthetic organisms (McKinlay and Harwood, 2010) [1]. RuBisCO has been the subject of a great deal of research over the years, but its progress is still constrained by the low activity of the RuBisCO enzyme (Timm et al., 2016) [2]. It has not yet been documented how tightly bound inhibitors induce decreased efficiency and how this is related to CO2. In our study, we investigated and validated the binding of five natural inhibitors and substrates to RuBisCO using a variety of analytical techniques such as accelerated molecular dynamics simulation (Perez et al., 2009) [3], binding free energy calculation (Sakae et al., 2020) [4], and protein interior analysis such as a dynamical cross-correlation matrix, a free energy landscape, a dictionary of secondary structure of proteins, and principal component analysis (Marelius et al., 1998) [5]. The results provided evidence in support of the tight binding and activity control of RuBisCO, in fact, The level of inhibitor binding ability calculated by us well echoes the level of inhibition (Frank et al., 1998; Zhu and Jensen, 1991; Keys et al., 1995; Pearce, 2006) [6–9] rate under physiological conditions, which reflects the accuracy of the calculation model. According to the results of the dynamic simulation, significant dynamic changes that occurred before and after the tight binding and were influenced by different aspects of the major and secondary structures were discovered. The analysis indicates that the close binding of the oxidation-produced inhibitor to RuBisCO was controlled by the interaction of key amino acids, the degree of bending of the inhibitor, and the critical LOOP area. Further, the CO2 simulation conditions (Tcherkez, 2016) [10] described the CO2 concentrating mechanism's carbon concentration mechanism and offered fresh insights into the RuBisCO enzyme (Andrews and Whitney, 2005) [11] (CCM). Analysis was done on CO2’s crucial function in the binding of RuBisCO.

The allosteric effect of the upper half of SENP1 contributes to its substrate selectivity for SUMO1 over SUMO2

SUMOylation regulates various cellular process and SENP1 (SUMO-specific protease 1) serves as a SUMO (small ubiquitin-related modifier) specific protease that participates in the SUMO cycle. Given its extensive influences on metabolic activities, SENP1 has gained more and more attentions in clinical treatments. However, there remains a question on why does the SENP1 prefer to process SUMO1 rather than SUMO2. Here, we performed molecular dynamics simulations of SENP1-SUMO1, SENP1-SUMO2, and apo SENP1 systems and observed distinct conformational dynamics in the upper half of the clamp and the three loops in the catalytic center of the SENP1. Principal component analysis revealed that the most prominent canonical variable represented the spatial distribution of the upper half of the clamp, while the openness of the cleft was closely related to the catalytic ability of SENP1. Further analysis of the SENP1-SUMO interactions revealed that the extensive and strong interactions between the SENP1 and SUMO1 were both in the interface of the upper half region and the catalytic center. Dynamic cross-correlation matrix analysis demonstrated that the inter-residue correlations in the SUMO1 system was much stronger, especially in the two essential regions belonging to the upper and lower half of cleft. Based on these observations, we proposed an allosteric propagation model and further testified it using the community analysis. These results revealed the propagation pathway of allosteric communication that contributed to the substrate discrimination of SENP1 upon SUMO1 and SUMO2. Communicated by Ramaswamy H. Sarma

Molecular dynamics simulations of the spike trimeric ectodomain of the SARS-CoV-2 Omicron variant: structural relationships with infectivity, evasion to immune system and transmissibility

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron is currently the most prevalent SARS-CoV-2 variant worldwide. Herein, we calculated molecular dynamics simulations of the trimeric spikeWT and SpikeBA.1 for 300 ns. Our results show that SpikeBA.1 has more conformational flexibility than SpikeWT. Our principal component analysis (PCA) allowed us to observe a broader spectrum of different conformations for SpikeBA.1, mainly at N-terminal domain (NTD) and receptor-binding domain (RBD). Such increased flexibility could contribute to decreased neutralizing antibody recognition of this variant. Our molecular dynamics data show that the RBDBA.1 easily visits an up-conformational state and the prevalent D614G mutation is pivotal to explain molecular dynamics results for this variant because to lost hydrogen bonding interactions between the residue pairs K854SC/D614SC, Y837MC/D614MC, K835SC/D614SC, T859SC/D614SC. In addition, SpikeBA.1 residues near the furin cleavage site are more flexible than in SpikeWT, probably due to P681H and D614G substitutions. Finally, dynamical cross-correlation matrix (DCCM) analysis reveals that D614G and P681H may allosterically affect the cleavage site S1/S2. Conversely, S2' site may be influenced by residues located between NTD and RBD of a neighboring protomer of the SpikeWT. Such communication may be lost in SpikeBA.1, explaining the changes of the cell tropism in the viral infection. In addition, the movements of the NTDWT and NTDBA.1 may modulate the RBD conformation through allosteric effects. Taken together, our results explain how the structural aspects may explain the observed gains in infectivity, immune system evasion and transmissibility of the Omicron variant. Communicated by Ramaswamy H. Sarma