Protein-ligand Interaction Profiling Research Articles

In silico analysis of the wild-type and mutant-type of BRCA2 gene

BackgroundThe aim of this study was to conduct an in silico analysis of a novel compound heterozygous variant in breast cancer susceptibility gene 2 (BRCA2) to clarify its structure–function relationship and elucidate the molecular mechanisms underlying triple-negative breast cancer (TNBC).MethodsA tumor biopsy sample was obtained from a 42-year-old Chinese woman during surgery, and a maxBRCA™ test was conducted using the patient’s whole blood. We obtained an experimentally determined 3D structure (1mje.pdb) of the BRCA2 protein from the Protein Data Bank (PDB) as a relatively reliable reference. Subsequently, the wild-type and mutant structures were predicted using SWISS-MODEL and AlphaFold, and the accuracy of these predictions was assessed through the SAVES online server. Furthermore, we utilized a high ambiguity-driven protein–protein docking (HADDOCK) algorithm and protein–ligand interaction profiler (PLIP) to predict the pathogenicity of the mutations and elucidate pathogenic mechanisms that potentially underlies TNBC.ResultsHistological examination revealed that the tumor biopsy sample exhibited classical pathological characteristics of TNBC. Furthermore, the maxBRCA™ test revealed two compound heterozygous BRCA2 gene mutations (c.7670 C > T.pA2557V and c.8356G > A.pA2786T). Through performing in silico structural analyses and constructing of 3D models of the mutants, we established that the mutant amino acids valine and threonine were located in the helical domain and oligonucleotide binding 1 (OB1), regions that interact with DSS1.ConclusionOur analysis revealed that substituting valine and threonine in the helical domain region alters the structure and function of BRCA2 proteins. This mutation potentially affects the binding of proteins and DNA fragments and disrupts interactions between the helical domain region and OB1 with DSS1, potentially leading to the development of TNBC. Our findings suggest that the identified compound heterozygous mutation contributes to the clinical presentation of TNBC, providing new insights into the pathogenesis of TNBC and the influence of compound heterozygous mutations in BRCA2.

Supramolecular clumps of μ2-1,3-acetate bridges of Cd(II)-Salen complex: Synthesis, spectroscopic characterization, crystal structure, DFT quantization's, and antifungal photodynamic therapy

The article divulges the crystal growth, synthesis, and X-ray structure characterization of one centrosymmetric cadmium complex, [Cd{CdL(μ2-1,3-acetate)}2] using Salen ligand (SL). The complex is further characterized using spectroscopic and analytical techniques, including DRS, SEM-EDX, PXRD, and ICP-MS. The crystallographic study showed that the complex has a monoclinic space P21/c. Addison parameters (Ʈ) show the hexagonal geometry of the central Cd(II) metal ion. Hirshfeld surface and 2-D fingerprint confirm supramolecular contacts despite weak C–H⋯O and C–H···π interactions. Energy frameworks, FMOs, global reactivity parameters, MEP, and energy bandgap explain the complex reactivity outlook. The complex inter- and intramolecular bonding interactions were explored through natural bond orbital (NBO), QTAIM, NCI-RDG, Electron Location Function (ELF), and Localized Orbital Locator (LOL) quantization methods. In addition, the complex and its synthetic components in vitro antibacterial efficacy were investigated using Gram-positive and Gram-negative microbial strains. SAR (structure-activity relationship) correlates with biological potency. Molecular docking assessed antimicrobial potency with proteins S. aureus (PDB ID: 1JIJ), C. albicans (PDB ID: 1M7A), E. coli (PDB ID: 1T9U), P. aeruginosa (PDB ID: 2UV0), and A. Niger (PDB ID: 3K4P). The findings are backed by the Protein-Ligand Interaction Profiler (PLIP). The antifungal potency and cell viability test of C. albicans were conducted using photodynamic therapy (APDT).

Trinuclear nickel (II) string complexes and copper (II) coordination polymer with pyrazine modulated unsymmetrical dipyridylamino ligand: Synthesis, structure and bioactivity properties with molecular docking

The unsymmetrical pyrazine-modulated ligand, N-(pyridine-2-yl)pyrazin-2-amine (Hppza) (1), its 1D straight-chain copper (II) coordination polymer [Cu2(Hppza)2∙(NO3)4]n (2) and trinuclear metal string [Ni3(µ3-ppza)4Cl2] (3) and [Ni3(µ3-ppza)4(NCS)2] (4) complexes have been successfully synthesized and structurally characterized. The free ligand Hppza (1) exhibits anti-syn conformation. In an asymmetric unit of 2, there are two kinds of Cu(II) atoms, both of which have elongated octahedral coordination geometry, and the copper(II) centers are linked by oxygen atoms of one nitrate anion. There are only minor differences in Ni…Ni bond lengths between pyrazine-modulated ligand complexes of [Ni3(μ3-ppza)4×2] (X = Cl− (3), NCS− (4)) and their unmodulated analogs, while the distances between the terminal nickel atoms and the axial ligands 3 and 4 are shorter. The results of magnetic susceptibility measurements showed an antiferromagnetic exchange constant (J) of about J = –199.2 cm–1 for 3 and J = –178.0 cm–1 for 4. The electrochemical properties of nickel strings of Hppza differ significantly from their unmodulated counterparts. The activities of ligands and their metal complexes against various proteins that are AChE (PDB ID: 4M0E), BChE (PDB ID: 5NN0), α-Gly (PDB ID: 1UAS), hCA I (PDB ID: 2CAB), and hCA II (PDB ID: 3DC3) were compared, and then the ADME/T properties of molecules were examined. Afterward, the interactions occurring in the docking calculation were examined in detail with the Protein-Ligand Interaction Profiler (PLIP) service. These complexes were inhibitors of BChE, hCA I and II, α-glycosidase and AChE enzymes for complex 3 and 5 with Ki values of 12.65 and 42.95 μM for hCA I, 3.64 and 15.84 μM for hCA II, 5.44 and 50.07 μM for BChE, 15.85 and 4.77 μM for α-glycosidase and 8.58 and 86.24 μM for AChE, respectively.

In silico docking study of selected compounds for its hepatoprotective activity

Liver fibrosis is a condition characterized by the excessive accumulation of scar tissue in the liver. It is typically caused by chronic liver diseases, such as chronic viral hepatitis (e.g., hepatitis B and C), alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), autoimmune hepatitis, and certain genetic conditions. Ephrin receptor A2 (EphA2) is identified as potential anti-inflammatory target which influences inflammatory process and immune response, impacting the recruitment and activation of immune cells and as a host cofactor for Hepatitis C Virus (HCV) entry. Andrographolide a diterpenoid lactone, Scoulerine a natural alkaloid possess anti-inflammatory activity. The present work was done to evaluate anti-inflammatory activity of andrographolide and scoulerine using software Autodock 4.2. Phyto-constituents were fetched from the PubChem database. 3D structure of EphA2 were downloaded from Protein Data Bank (PDB). Among two phyto compounds, andrographolide had highest binding energy of -7.58 which is a clear evident of potential anti-inflammatory activity and prevent hepatic fibrosis. The active site of the target protein was predicted by using CASTP (Computed atlas of surface topography of proteins). Protein ligand interaction information is obtained by Protein ligand interaction profiler.

Protein structure prediction based on deep learning: HER2 in complex with a covalent inhibitor

HER2 protein overexpression is associated with the malignant degree and poor prognosis of breast cancer. HER2 levels are elevated in 20% of breast tumors. Several covalent tyrosine kinase inhibitors have been found to reduce tumor cell survival and proliferation in vitro and inhibit downstream HER2 signaling. In the field of protein structure prediction, AlphaFold2, which achieved excellent results in CASP14, can periodically predict protein structures with atomic precision in the absence of similar protein structures. In this study, AlphaFold2 was used to predict the monomeric structure of the HER2 protein. This predicted structure was compared to the conformation of HER2 in complex with a covalent inhibitor, allowing for an examination of the conformational changes induced by the inhibitor. By combining the conformational changes of HER2 protein with the docking results of Protein-Ligand Interaction Profiler, other potential binding sites were identified, which could further reveal the mechanism of drug discovery.

In silico and in vitro evaluation of the anti-virulence potential of patuletin, a natural methoxy flavone, against Pseudomonas aeruginosa.

This study aimed to investigate the potential of patuletin, a rare natural flavonoid, as a virulence and LasR inhibitor against Pseudomonas aeruginosa. Various computational studies were utilized to explore the binding of Patuletin and LasR at a molecular level. Molecular docking revealed that Patuletin strongly interacted with the active pocket of LasR, with a high binding affinity value of -20.96 kcal/mol. Further molecular dynamics simulations, molecular mechanics generalized Born surface area (MM/GBSA), protein-ligand interaction profile (PLIP), and essential dynamics analyses confirmed the stability of the patuletin-LasR complex, and no significant structural changes were observed in the LasR protein upon binding. Key amino acids involved in binding were identified, along with a free energy value of -26.9 kcal/mol. In vitro assays were performed to assess patuletin's effects on P. aeruginosa. At a sub-inhibitory concentration (1/4 MIC), patuletin significantly reduced biofilm formation by 48% and 42%, decreased pyocyanin production by 24% and 14%, and decreased proteolytic activities by 42% and 20% in P. aeruginosa isolate ATCC 27853 (PA27853) and P. aeruginosa clinical isolate (PA1), respectively. In summary, this study demonstrated that patuletin effectively inhibited LasR activity in silico and attenuated virulence factors in vitro, including biofilm formation, pyocyanin production, and proteolytic activity. These findings suggest that patuletin holds promise as a potential therapeutic agent in combination with antibiotics to combat antibiotic-tolerant P. aeruginosa infections.

In-silico Investigations for the Identification of Novel Inhibitors Targeting Hepatitis C Virus RNA-dependent RNA Polymerase.

Hepatitis C is an inflammatory condition of the liver caused by the hepatitis C virus, exhibiting acute and chronic manifestations with severity ranging from mild to severe and lifelong illnesses leading to liver cirrhosis and cancer. According to the World Health Organization's global estimates, a population of about 58 million have chronic hepatitis C virus infection, with around 1.5 million new infections occurring every year. The present study aimed to identify novel molecules targeting the Hepatitis C viral RNA Dependent RNA polymerases, which play a crucial role in genome replication, mRNA synthesis, etc. Methods: Structure-based virtual screening of chemical libraries of small molecules was done using AutoDock/Vina. The top-ranking pose for every ligand was complexed with the protein and used for further protein-ligand interaction analysis using the Protein-ligand interaction Profiler. Molecules from virtual screening were further assessed using the pkCSM web server. The proteinligand interactions were further subjected to molecular dynamics simulation studies to establish dynamic stability. Molecular docking-based virtual screening of the database of small molecules, followed by screening based on pharmacokinetic and toxicity parameters, yielded eight probable RNA Dependent RNA polymerase inhibitors. The docking scores for the proposed candidates ranged from - 8.04 to -9.10 kcal/mol. The potential stability of the ligands bound to the target protein was demonstrated by molecular dynamics simulation studies. Data from exhaustive computational studies proposed eight molecules as potential anti-viral candidates, targeting Hepatitis C viral RNA Dependent RNA polymerases, which can be further evaluated for their biological potential.

In vitro and in silico correlation of benzoxazole-based thiazolidinone hybrids derivatives: A promising acetylcholinesterase and butyrylcholinesterase inhibitors

Benzoxazole-based thiazolidinone hybrids derivatives (1–19) were afforded and further subjected to in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition studies for the first time. All these analogues were found to display good inhibition against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE)enzymes with IC50 values 4.20 ± 1.10 µM to 43.20 ± 4.50 µM (against AChE) and 3.80 ± 1.20 µM to 34.50 ± 3.30 µM (against BuChE) as compared to standard donepezil having IC50 values of 21.86 ± 0.40 µM (against AChE) and 32.47 ± 2.30 µM (against BuChE) respectively. Specifically, compound 16, characterized by a 3,4-dichloro substitution on ring B and 2–OH and 4-CF3 substitutions on ring C, along with compound 13, having 2,4-diCl on ring B and 2-OH and 4-CF3 on ring C, were identified as the most potent inhibitors of the targeted AChE and BuChE enzymes, even manifolds more potent than standard donepezil drug. The structures of all synthesized analogues were verified through the utilization of multiple spectroscopic techniques, including HREI-MS and NMR (1H NMR and 13C NMR). The structure-activity relationship (SAR) demonstrated that analogs bearing electron withdrawing groups such as –CF3, –Cl and -NO2 groups displayed superior AChE and BuChE activities. In the molecular docking analysis of the most potent analogs, a favorable protein-ligand interaction (PLI) profile was observed with the respective targets (AChE and BuChE). These interactions encompassed crucial bonding types such as hydrogen bonding, π-π interactions, π-π stacking, and hydrophobic interactions.

In silico identification and characterization of small molecule binding to the CD1d immunoreceptor

CD1 immunoreceptors are a non-classical major histocompatibility complex (MHC) that present antigens to T cells to elucidate immune responses against disease. The antigen repertoire of CD1 has been composed primarily of lipids until recently when CD1d-restricted T cells were shown to be activated by non-lipidic small molecules, such as phenyl pentamethyl dihydrobenzofuran sulfonate (PPBF) and related benzofuran sulfonates. To date structural insights into PPBF/CD1d interactions are lacking, so it is unknown whether small molecule and lipid antigens are presented and recognized through similar mechanisms. Furthermore, it is unknown whether CD1d can bind to and present a broader range of small molecule metabolites to T cells, acting out functions analogous to the MHC class I related protein MR1. Here, we perform in silico docking and molecular dynamics simulations to structurally characterize small molecule interactions with CD1d. PPBF was supported to be presented to T cell receptors through the CD1d F’ pocket. Virtual screening of CD1d against more than 17,000 small molecules with diverse geometry and chemistry identified several novel scaffolds, including phytosterols, cholesterols, triterpenes, and carbazole alkaloids, that serve as candidate CD1d antigens. Protein-ligand interaction profiling revealed conserved residues in the CD1d F’ pocket that similarly anchor small molecules and lipids. Our results suggest that CD1d could have the intrinsic ability to bind and present a broad range of small molecule metabolites to T cells to carry out its function beyond lipid antigen presentation. Communicated by Ramaswamy H. Sarma

Evaluation of therapeutic potentials of some bioactive compounds in selected African plants targeting main protease (Mpro) in SARS-CoV-2: a molecular docking study

BackgroundCoronavirus disease 2019 (COVID-19) is an infectious disease brought on by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a global treat in early 2020. Despite worldwide research proving different medications used to treat COVID-19, the infection still affects the human race; we need to continue researching the virus to protect humanity and reduce the complications that some medications might cause. This study focuses on finding another promising therapeutic compound against SARS-CoV-2. Twenty-four (24) bioactive compounds were selected from the following African plants' Adansonia digitata L, Aframomum melegueta K. Schum, Ageratum conyzoides (L.) L, and Boswellia dalzielii, and Remdesivir was used as the control medication. The PubChem web server acquired the 3D structures of bioactive compounds in the plant and the control medication. The SARS-CoV-2 main protease (Mpro) crystal structure was obtained using the Protein Data Bank (PDB). Using the SwissADME web server, the bioactive compounds' drug-likeness was assessed, and AutoDock was employed for the molecular docking with the Mpro. The Proteins Plus and Protein–Ligand Interaction Profiler web servers were used to analyse the docked complexes. Furthermore, the admetSAR website was utilized to predict the ligands' absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties.ResultsBased on the drug-likeness screening, Rutin violated more than one of the Lipinski rules of five, while Remdesivir violated two. Molecular docking analysis results indicated that Catechin, Epicatechin, Vitexin, Quercetin, Kaempferol, Gamma-Sitosterol, and Kaur-16-ene exhibited a stronger binding affinity with Mpro, with binding scores of − 7.1, − 7.1, − 8.0, − 7.3, − 7.2, − 6.8, and − 6.5 kcal/mol, respectively, compared to Remdesivir's binding score of − 6.3 kcal/mol. Consequently, binding scores of bioactive compounds suggest their potential biological activity against the SARS-CoV-2 main protease. Additionally, these bioactive compounds exhibited favourable ADMET properties. Vitexin also has a plasma protein binding below 90%, a promising medication distribution feature.ConclusionsThis study shows that Catechin, Epicatechin, Vitexin, Quercetin, Kaempferol, Gamma-Sitosterol, and Kaur-16-ene have better binding affinities with Mpro than Remdesivir. Molecular dynamics simulation in vitro and in vivo investigation is required to support this study.

Nanomolar Protein Thermal Profiling with Modified Cyanine Dyes.

Protein properties and interactions have been widely investigated by using external labels. However, the micromolar sensitivity of the current dyes limits their applicability due to the high material consumption and assay cost. In response to this challenge, we synthesized a series of cyanine5 (Cy5) dye-based quencher molecules to develop an external dye technique to probe proteins at the nanomolar protein level in a high-throughput one-step assay format. Several families of Cy5 dye-based quenchers with ring and/or side-chain modifications were designed and synthesized by introducing organic small molecules or peptides. Our results showed that steric hindrance and electrostatic interactions are more important than hydrophobicity in the interaction between the luminescent negatively charged europium-chelate-labeled peptide (Eu-probe) and the quencher molecules. The presence of substituents on the quencher indolenine rings reduces their quenching property, whereas the increased positive charge on the indolenine side chain improved the interaction between the quenchers and the luminescent compound. The designed quencher structures entirely altered the dynamics of the Eu-probe (protein-probe) for studying protein stability and interactions, as we were able to reduce the quencher concentration 100-fold. Moreover, the new quencher molecules allowed us to conduct the experiments using neutral buffer conditions, known as the peptide-probe assay. These improvements enabled us to apply the method in a one-step format for nanomolar protein-ligand interaction and protein profiling studies instead of the previously developed two-step protocol. These improvements provide a faster and simpler method with lower material consumption.

Researching of resistance to etravirine in some HIV-1 low-level viremia strains by in-silico methods

Abstract Objectives Human immunodeficiency virus (HIV) is a significant infection that attacks immune system cells and integrates its genetic material into host cells. Left untreated, it leads to acquired immunodeficiency syndrome (AIDS). Antiretroviral therapy (ART) is used to control HIV infection. Etravirine (ETR) is an important non-nucleoside reverse transcriptase inhibitor (NNRTI) utilized in the treatment of HIV. Low-level viremia (LLW) is a serious clinical condition, and the underlying mechanisms remain incompletely understood. The aim of our study is to analyze and elucidate the resistance status of Lys104Gln, Lys102Gln, Lys101Arg-Lys104Arg, Ser191Phe, Ile94Leu-Lys104Arg, Lys104Glu-His235Leu, Ala98Ser and Val179Ile mutations using in-silico methods, which are identified as low-level viremic strains, because their resistance status to ETR is unknown. Methods Homology modeling was performed using the Swiss Model program. Molecular docking of ETR with the reverse transcriptase (RT) enzyme was conducted using the CB-Dock program developed by AutoDock Vina. Protein-ligand interaction analysis was carried out using the protein-ligand interaction profiler (PLIP). Results A98S and V179I mutations altered the physicochemical properties of the region, resulting in changes to the conformational structure of the NNRTI hydrophobic pocket compared to the wild-type and consequently decreased docking scores. Conclusions Based on the evaluation of literature data and in-silico analyses, it is believed that A98S and V179I mutations may alter the conformational structure of the hydrophobic pocket where ETR binds, potentially resulting in low-level resistance against ETR.

Phenothiazine-based virtual screening, molecular docking, and molecular dynamics of new trypanothione reductase inhibitors of Trypanosoma cruzi.

Phenothiazine derivatives can unselectively inhibit the trypanothione-dependent antioxidant system enzyme trypanothione reductase (TR). A virtual screening of 2163 phenothiazine derivatives from the ZINC15 and PubChem databases docked on the active site of T. cruzi TR showed that 285 compounds have higher affinity than the natural ligand trypanothione disulfide. 244 compounds showed higher affinity toward the parasite's enzyme than to its human homolog glutathione reductase. Protein-ligand interaction profiling predicted that the main interactions for the top scored compounds were with residues important for trypanothione disulfide binding: Phe396, Pro398, Leu399, His461, Glu466, and Glu467, particularly His461, which participates in catalysis. Two compounds with the desired profiles, ZINC1033681 (Zn_C687) and ZINC10213096 (Zn_C216), decreased parasite growth by 20 % and 50 %, respectively. They behaved as mixed-type inhibitors of recombinant TR, with Ki values of 59 and 47 μM, respectively. This study provides a further understanding of the potential of phenothiazine derivatives as TR inhibitors.

Bioinformatics analysis of wild-type ParC and S79F, S79Y mutations in Streptococcus pneumoniae.

S79Y and S79F mutations in ParC at the fluoroquinolone binding site confer resistance to quinolones in Streptococcus pneumoniae. The aim of this study was to perform bioinformatics analysis of wild-type and mutant ParC identified in S. pneumoniae strains. Homology models were created with Swiss Model, and the UCSF Chimera was used for the analysis and evaluation of the models. Molecular docking studies and protein-ligand interaction analysis were performed using CB-Dock developed by AutoDock Vina and Protein Ligand Interaction Profiler (PLIP), respectively. According to the homology modeling results, changes were observed in the physicochemical properties. Both mutant types showed a decrease in hydrophobicity (S79F: 2.0, S79Y: 0.5 - Kyte-Doolittle) and an increase in regional volume (S79F: 95 Å3, S79Y: 100 Å3). The docking scores for the wild-type, S79F, and S79Y types were 6.3, 4.9, and 5.0, respectively. The decrease in docking scores indicates weaker binding in the mutant types. The results of the PLIP analysis indicate that new bonds were formed, and the bond types changed in both mutant types, while some bonds disappeared. It is believed that the change in physicochemical properties caused by the mutation altered the conformation of the quinolone binding region and the bond types, numbers, and proximities of the amino acids involved in the interaction with the active substance. The results obtained from the modeling performed in this study with visualization and analysis of possible conformational, hydrophobic, and volumetric changes of only ParC mutations provided data and literature support to elucidate the mechanism. The molecular docking and PLIP results obtained in this study support both the homology modeling results and the fact that S79F and S79Y have been shown to be resistant in the literature.

CSC01 shows promise as a potential inhibitor of the oncogenic G13D mutant of KRAS: an in silico approach.

About 30% of malignant tumors include KRAS mutations, which are frequently required for the development and maintenance of malignancies. KRAS is now a top-priority cancer target as a result. After years of research, it is now understood that the oncogenic KRAS-G12C can be targeted. However, many other forms, such as the G13D mutant, are yet to be addressed. Here, we used a receptor-based pharmacophore modeling technique to generate potential inhibitors of the KRAS-G13D oncogenic mutant. Using a comprehensive virtual screening workflow model, top hits were selected, out of which CSC01 was identified as a promising inhibitor of the oncogenic KRAS mutant (G13D). The stability of CSC01 upon binding the switch II pocket was evaluated through an exhaustive molecular dynamics simulation study. The several post-simulation analyses conducted suggest that CSC01 formed a stable complex with KRAS-G13D. CSC01, through a dynamic protein-ligand interaction profiling analysis, was also shown to maintain strong interactions with the mutated aspartic acid residue throughout the simulation. Although binding free energy analysis through the umbrella sampling approach suggested that the affinity of CSC01 with the switch II pocket of KRAS-G13D is moderate, our DFT analysis showed that the stable interaction of the compound might be facilitated by the existence of favorable molecular electrostatic potentials. Furthermore, based on ADMET predictions, CSC01 demonstrated a satisfactory drug likeness and toxicity profile, making it an exemplary candidate for consideration as a potential KRAS-G13D inhibitor.

Computational Investigation of GluN2B Receptor Effectiveness of Octreotide in Nervous Diseases by Using AutoDock Vina

: The N-methyl-D-aspartate (NMDA) receptors are ionotropic glutamate receptors that participate in excitatory postsynaptic signaling in the mammalian central nervous system. In the 1980s, octreotide first became available for the treatment of acromegaly. In acromegaly patients and healthy volunteers, somatostatin and its analogs, such as octreotide and lanreotide, dramatically decrease the release of GH. In this study, we investigated the effect of octreotide, which controls blood lipids, on one of the proteins involved in epilepsy. After examining the genes involved in epilepsy by the DisGeNET server, we selected the ionotropic glutamate receptor NMDA type subunit 2B gene with the symbol GRIN2B. The docking and molecular simulation process was done using the AutoDock Vina 1.2.0 algorithm under the Chimera user interface. The analysis of docking results has been done by the PDBsum and Protein-Ligand Interaction Profiler servers. The VMD program prepared the images. The Pocket Drug server detected eighteen packets. Only the molecular docking results of 5 out of 18 pockets were acceptable. The results of docking for eighteen pockets were found in the target protein after the simulations; 13 have fewer than 14 residues, and 5 have more than 14 residues. We selected the best 18 pockets (P35, P64), (P10, P14, P17).

Repurposing of neprilysin inhibitor ‘sacubitrilat’ as an anti-cancer drug by modulating epigenetic and apoptotic regulators

Modifications in the epigenetic landscape have been considered a hallmark of cancer. Histone deacetylation is one of the crucial epigenetic modulations associated with the aggressive progression of various cancer subtypes. Herein, we have repurposed the neprilysin inhibitor sacubitrilat as a potent anticancer agent using in-silico protein–ligand interaction profiler (PLIP) analysis, molecular docking, and in vitro studies. The screening of PLIP profiles between vorinostat/panobinostat and HDACs/LTA4H followed by molecular docking resulted in five (Sacubitrilat, B65, BDS, BIR, and NPV) FDA-approved, experimental and investigational drugs. Sacubitrilat has demonstrated promising anticancer activity against colorectal cancer (SW-480) and triple-negative breast cancer (MDA-MB-231) cells, with IC50 values of 14.07 μg/mL and 23.02 μg/mL, respectively. FACS analysis revealed that sacubitrilat arrests the cell cycle at the G0/G1 phase and induces apoptotic-mediated cell death in SW-480 cells. In addition, sacubitrilat inhibited HDAC isoforms at the transcriptomic level by 0.7–0.9 fold and at the proteomic level by 0.5–0.6 fold as compared to the control. Sacubitrilat increased the protein expression of tumor-suppressor (p53) and pro-apoptotic makers (Bax and Bid) by 0.2–2.5 fold while decreasing the expression of anti-apoptotic Bcl2 and Nrf2 proteins by 0.2–0.5 fold with respect to control. The observed cleaved PARP product indicates that sacubitrilat induces apoptotic-mediated cell death. This study may pave the way to identify the anticancer potential of sacubitrilat and can be explored in human clinical trials.

Synthesis of novel Cu(II) complexes with N2O2 ligands: Characterization, theoretical calculations, antimicrobial, antioxidant, DNA binding, and in vitro anticancer activity studies

The aim was to investigate the in vitro antimicrobial, antioxidant, cytotoxic activities and pBR322 Plasmid DNA interaction potentials of newly synthesized Schiff bases and their copper complexes. Cytotoxic activities of these compounds were determined by MTT methods in human breast cancer (MCF-7), human cervical cancer (HeLa) and mouse fibroblast (L929) cell lines. The determination of changes in oxidant and antioxidant load of the cell after application of these compounds were investigated with the aid of Rel Assay Diagnostics kits. It was found that the some of the compounds had moderate antimicrobial activity, and oxidative stress index. According to plasmid DNA interaction studies, synthesized complexes modified the tertiary structure of pBR322 plasmid DNA. The compound Bis-Napht showed the highest cytotoxic activity in HeLa, MCF-7 and L929 cells at an IC50 dose of 3 ± 1 µM, 5 ± 1 µM and 3 ± 1 µM respectively. Compound Bis-Sal was determined to have lower cytotoxic activity in L-929 cells at an IC50 dose of 106 ± 9 µM at 24 h compared to other compounds. Ligand compounds and their metal complexes were optimized on the B3LYP, HF, and M06-2x methods with the 6–31++g(d,p) basis set. Afterwards, their activities were compared against crystal structure of the BRCT repeat region from the breast cancer associated protein, (BRCA1) (PDB ID: 1JNX) and crystal Structure of CDK2 receptor of cervical cancer cell proteins (PDB ID: 4BGH). To examine the interactions occurring in more detail, Protein-Ligand Interaction Profiler analysis was performed and all chemical interactions that occurred were determined.

Exploring Metabolites Of Green Algae Caulerpa Spp. To Discover Putative Inhibitors Of Dpp-4, A New Antidiabetic Target Protein

Diabetes mellitus (DM) remains a serious global health threat, claiming a million lives every year and affecting nearly 9% of the adult population who suffer from this impaired insulin sensitivity disease. The Dipeptidyl peptidase-4 (DPP-4) enzyme has recently attracted attention because of its crucial role in insulin signaling, making this enzyme an interesting and emerging target for antidiabetic drug discovery. This study aimed to explore reported metabolites from marine algae of the genus Caulerpa as DPP-4 inhibitors through computational studies using CB-dock 2, Protein-Ligand Interaction Profiler, SwissAdme, and pkCMS. Molecular docking allowed the identification of 7 hit compounds with strong binding affinities (8.4 kcal to 9.3 kcal/mol) against DPP-4 target enzyme PDB ID: 3G4I. Four hits showed stronger binding affinity than two DPP-4 specific inhibitors and FDA-approved antidiabetic drugs, sitagliptin (8.4 kcal/mol) and linagliptin (9.0 kcal/mol). Following a molecular modification of the hit compounds using a bioisosterism-like approach and ADMET evaluation with pkCMS, three putative DPP-4 inhibitors were identified. They showed either stronger binding affinities or better ADMET profiles than sitagliptin and linagliptin, suggesting their promising potential as DPP-4 inhibitors. However, further optimized bioisoterism, in silico and in vivo studies, and clinical-based trials are required to confirm their antidiabetic activity. Keywords: Antidiabetic, Caulerpa racemosa, caulerpin, DPP-4

Virtual Screening of Novel Phytocompound(s) with Potential to Combat Mycobacterium tuberculosis Infection

Background: Tuberculosis is a worldwide health concern, and there is an immediate need for effective therapeutics to inhibit the infection caused by Mycobacterium tuberculosis. The persistent state of bacteria and the emergence of Multi-Drug Resistance are the two major reasons for the difficulty in treating tuberculosis. Objective: The study aims to identify novel phytocompounds to effectively inhibit Mycobacterium tuberculosis by targeting the Esx-1 protein, which plays a vital function in the secretion pathway of M. tuberculosis to successfully disrupt the host cell and cause tuberculosis. Method: In the current study, ~500 novel phytocompounds were screened by docking against Esx-1 using AutoDock Vina 4.2 version. The visualization analysis for selected phytocompounds was performed using Protein-Ligand Interaction Profiler. A comparative study with a well-known drug for tuberculosis, Rifampicin, was also performed. Moreover, ADMET analysis was performed to check the druggability and pharmacokinetic parameters of the selected compounds. Result: Based on the analysis, cadabicine, an alkaloid produced by Cadaba fruticose (Vizhuthi), Crataeva nurvala (Varuna) plants, exhibits the best binding affinity of -7.8 Kcal/mol with the active site residues, Leu 29 and Trp 43, of Esx-1, which are required for the stability of Esx-1 and virulence of M. tuberculosis in the host cell. ADMET analysis showed that cadabicine exhibits better druggability and pharmacokinetic parameters than other selected compounds. Conclusion: Cadabicine possesses an acceptable binding affinity with the active site of Esx-1 and exhibits acceptable physicochemical and pharmacokinetic properties, which makes it a potential new drug candidate for the treatment of tuberculosis.