Human MRP1 protein plays a vital role in cancer multidrug resistance. Coumarins show promising pharmacological properties. Virtual screening, ADMET, molecular docking and molecular dynamics (MD) simulations were utilized as pharmacoinformatic tools to identify potential MRP1 inhibitors among coumarin derivatives. Using in silico ADMET, 50 hits were further investigated for their selectivity toward the nucleotide-binding domains (NBDs) of MRP1 using molecular docking. Accordingly, coumarin, its symmetrical ketone derivative Lig. No. 4, and Reversan were candidates for focused docking study with the NBDs domains compared with ATP. The result indicates that Lig. No. 4, with the best binding score, interacts with NBDs via hydrogen bonds with residues: GLN713, LYS684, GLY683, CYS682 in NBD1, and GLY1432, GLY771, SER769 and GLN1374 in NBD2, which mostly overlap with ATP binding residues. Moreover, doxorubicin (Doxo) was docked to the transmembrane domains (TMDs) active site of MRP1. Doxo interaction with TMDs was subjected to MD simulation in the NBDs free and occupied with Lig. No. 4 states. The results showed that Doxo interacts more strongly with TMD residues in inward facing feature of TMDs helices. However, when Lig. No. 4 exists in NBDs, Doxo interactions are different, and TMD helices show more outward-facing conformation. This result may suggest a partial competitive inhibition mechanism for the Lig. No. 4 on MRP1 compared with ATP. So, it may inhibit active complex formation by interfering with ATP entrance to NBDs and locking MRP1 conformation in outward-facing mode. This study suggests a valuable coumarin derivative that can be further investigated for potent MRP1 inhibitors.Communicated by Ramaswamy H. Sarma.

Cyclic peptides (CPs) are a promising class of drugs because of their high biological activity and specificity. However, the design of CP remains challenging due to their conformational flexibility and difficulties in designing stable binding conformation. Herein, we present a high-throughput MD screening (HTMDS) process for the iterative design of stable CP binders with a combinatorial CP library composed of canonical and non-canonical amino acids. As a proof of concept, we apply our methods to design CP inhibitors for the bromodomain (BrD) of ATAD2B. 698,800 CP candidates with a total of 25,570 ns MD simulations were performed to study the protein-ligand binding interactions. The binding free energies (ΔGbind) estimated by MM/PBSA approach for eight lead CP designs were found to be low. CP-1st.43 was the best CP candidate with an estimated ΔGbind of -28.48 kcal/mol when compared to the standard inhibitor C-38 which has been experimentally validated and shown to exhibit ΔGbind of -17.11 kcal/mol. The major contribution of binding sites for BrD of ATAD2B involved the hydrogen-bonding anchor within the Aly-binding pocket, salt bridging, and hydrogen-bonding mediated stabilization of the ZA loop and BC loop, and the complementary Van der Waals attraction. Our methods demonstrate encouraging results by yielding conformationally stable and high-potential CP binders that should have potential applicability in future CP drug development.Communicated by Ramaswamy H. Sarma.

Erratum in J Biomol Struct Dyn. 2023 May 27;:1.

In order to know the insights of a unique naturally existing trimodular licheninase from GH16 family, sub-family 21 (RfGH16_21) from Ruminococcus flavefaciens, its structure was modeled to understand its functional relations to reveal information regarding modifying the enzyme for improved properties with enhanced catalytic efficiency. Homology modeling revealed three tandem repeats of β-jelly roll like folds linked by natural linkers. Catalytic pockets and the catalytically important amino acids in each tandem repeat of RfGH16_21 determined by multiple sequence alignment and structure superposition with its homologues indicated that two Glu residues are involved in a retaining-type of catalytic mechanism. Sequential molecular docking revealed maximum binding energy with mixed linked cellotriose showing that cellotriose is the lowest oligomeric hydrolysed product formed by the catalytic action of endo-β-1,3-1,4-glucanase. Molecular dynamic (MD) simulation of RfGH16_21-cellotriose complex confirmed the structural specificity of catalytic residues and increased stability of enzyme in presence of ligand as compared to simulated RfGH16_21 alone. The binding affinity of cellotriose towards the three tandem repeats of RfGH16_21 was also confirmed by calculating total binding Gibbs free energy, i.e. -100.8 ± 2.6 KJ/mol, by using g_mmpbsa tool. The stability of the protein was determined by protein melting analysis that showed Ca2+ and Mg2+ ions imparted structural stability to RfGH16_21. Dynamic light scattering analysis of RfGH16_21 showed monodispersity and hydrodynamic radius of 4.0 nm at 2.0 mg/mL protein concentration, which was comparable with the radius of gyration of 3.2 nm determined by MD simulation showing the protein to be in monomeric form.Communicated by Ramaswamy H. Sarma.

Histone deacetylases (HDACs) are critical epigenetic drug targets that have gained significant attention in the scientific community for the treatment of cancer. The currently marketed HDAC inhibitors lack selectivity for the various HDAC isoenzymes. Here, we describe our protocol for the discovery of novel potential hydroxamic acid based HDAC3 inhibitors through pharmacophore modeling, virtual screening, docking, molecular dynamics (MD) simulation and toxicity studies. The ten pharmacophore hypotheses were established, and their reliability was validated by different ROC (receiving operator curve) analysis. Among them, the best model (Hypothesis 9 or RRRA) was employed for searching SCHEMBL, ZINC and MolPort database to screen out hit molecules as selective HDAC3 inhibitors, followed by different docking stages. MD simulation (50 ns) and MMGBSA study were performed to study the stability of ligand binding modes and with the help of trajectory analysis, to calculate the ligand-receptor complex RMSD (root-mean-square deviation), RMSF (root-mean-square fluctuation) and H-bond distance, etc. Finally, in-silico toxicity studies were performed on top screened molecules and compared with reference drug SAHA and established structure-activity relationship (SAR). The results indicated that compound 31, with high inhibitory potency and less toxicity (probability value 0.418), is suitable for further experimental analysis.Communicated by Ramaswamy H. Sarma.

Erratum in J Biomol Struct Dyn. 2023 Apr 27;:1. J Biomol Struct Dyn. 2023 Sep-Oct;41(16):ii. J Biomol Struct Dyn. 2023 Sep-Oct;41(16):iii. J Biomol Struct Dyn. 2023 Sep-Oct;41(16):iv.

Researchers are investigating the medicinal properties of herbal plants throughout the world, which often leads to the discovery of novel plants and their chemicals for prophylactic needs of humans. Natural phytochemicals continue to be sought as alternative treatments for various diseases because of their non-toxic and therapeutic properties. In recent years, computational phytochemistry has enabled large-scale screening of phytochemicals, enabling researchers to pursue a wide range of therapeutic research alternatives to traditional ethnopharmacology. We propose to identify an anti-diabetic plant by computational screening on Indian herbal plants in conjunction with experimental characterization and biological validation. The methodology involves the creation of an in-house Indian herbal plant database. Molecular docking is used to screen against alpha amylase for anti-diabetic prophylaxis. Cassia angustifolia was chosen because its phytochemicals are able to bind to alpha amylase. Plants were experimentally extracted, botanically studied and their biological activity was evaluated. Further, the use of molecular dynamics was then applied to pinpoint the phytochemicals responsible for the affinity of alpha amylase. Results in the phytochemical analysis of the extracts revealed strong presence of alkaloids, flavonoids and cardiac glycosides. Moreover, alpha amylase biological activity with C. angustifolia extracts of chloroform, hexane and ethyl acetate demonstrated activity of 3.26, 8.01 and 30.33 µg/ml validating computational predictions. In conclusion, this study developed, validated computational predictions of identifying potential anti-diabetic plants 'Cassia angustifolia' from house herbal databases. Hope this study shall inspire explore plant therapeutic repurposing using computational methods of drug discovery.Communicated by Ramaswamy H. Sarma.

The inhibitory effects of ferulic and chlorogenic acids on tyrosinase activity were investigated through multi-spectroscopic and molecular docking techniques. Ferulic and chlorogenic acids, flavonoid compounds, demonstrated inhibitory monophenolase activities of tyrosinase. The inhibitor effects against monophenolase activity were in a reversible and competitive manner with ki value equal to 6.8 and 7.5 µM respectively. The affinity between tyrosinase and L-DOPA decreased when fatty acids were added to the solution. The multi-spectroscopic techniques like UV-vis, fluorescence, and isothermal calorimetry are employed to investigate changes. Intrinsic fluorescence quenching and conformational changes of tyrosinase by hydrophobic interaction were confirmed. Tyrosinase had two and three binding sites for ferulic and chlorogenic acids with a binding constant in the order of magnitude of -6.8 and -7.2 kcal/mol. In addition, the secondary structural changes with Circular dichroism (CD) analysis, secondary structure (DSSP), radius of gyration (Rg) and analysis of hydrogen bonds (H-bonds) confirmed. Ferulic acid effect can be observed obviously and also content of α-helix decreased. Thermodynamic parameters indicated that the interaction between enzyme and ferulic and chlorogenic acids followed a spontaneous reaction dynamic manner with ΔG = -14.78 kJ/mol and ΔG = -14.61 kJ/mol (298k). The findings highlighted the potential applications of ferulic acid and chlorogenic acids in food and drug industries as potent inhibitors of tyrosinase.Communicated by Ramaswamy H. Sarma.

Erratum in J Biomol Struct Dyn. 2023 Sep-Oct;41(16):iii.

Erratum in J Biomol Struct Dyn. 2023 Jul 18;:1.

Since the design of metal complexes with better biological activities is important, herein a new palladium(II) complex bearing en and acac (en and acac stand for ethylenediamine and acetylacetonato, respectively) as its ligands, [Pd(en)(acac)]NO3 complex, was synthesized and fully characterized. Quantum chemical computations of the palladium(II) complex were done via DFT/B3LYP method. Cytotoxicity activity of the new compound on leukemia cell line (K562) was assessed via MTT method. The findings indicated that the metal complex has remarkable cytotoxic effect than cisplatin. OSIRIS DataWarrior software was employed to calculate in-silico physicochemical and toxicity parameters of the synthesized complex which rendered significant results. To comprehend the interaction type of new metal compound with macromolecules, the in depth investigation of interaction of mentioned complex with CT-DNA and BSA was accomplished by fluorescence, UV-Visible absorption spectroscopy, viscosity measurement, gel electrophoresis, FRET analysis and circular dichroism (CD) spectroscopy. On the other hand, computational molecular docking was carried out and the obtained data demonstrated that H-bond and van der Waals forces are the dominant forces for the binding of the compound to the mentioned biomolecules. Molecular dynamics simulation was also done and confirmed the stability of best docked pose of palladium(II) complex inside DNA or BSA over the time and in presence of water solvent. Also, Our own N-layered Integrated molecular Orbital and molecular Mechanics (ONIOM) methodology based on the hybridization of quantum mechanics and molecular mechanics (QM/MM) methodology was accomplished to inquire about binding of Pd(II) complex with DNA or BSA.Communicated by Ramaswamy H. Sarma.

Erratum in J Biomol Struct Dyn. 2023 Sep-Oct;41(16):iv.

The proteolytic enzyme 3 C-like protease (3Clpro or Mpro) is considered the most important target for SARS-CoV-2 which could be attributed to its crucial role in viral maturation and/or replication. Besides, natural phytoconstituents from plant origin are always promising lead compounds in the drug discovery area. Herein, the previously isolated and identified seven compounds from Jasminum humile (J. humile) were examined in vitro and in silico against the SARS-CoV-2 Mpro. First, the Vero E6 cells were utilized to pursue the potential of the investigated compounds (both in fractions and individual isolates) using the MTT assay. The total extract (T1) displayed the most significant activity against SARS-CoV-2 with IC50 = 29.36 µg/mL. Besides, the fractions (Fr1 and Fr3) showed good activity against the SARS-CoV-2 with IC50 values of 70.42, and 73.09 µg/mL, respectively. Then, the SARS-CoV-2 Mpro inhibitory assay was utilized to emphasize the inhibitory potential of the investigated isolates. MJN, JMD, and IJM candidates displayed prominent Mpro inhibitory potentials with IC50 = 30.44, 30.24, and 56.25 µM, respectively. Moreover, molecular docking of the identified seven compounds against the Mpro of SARS-CoV-2 showed that the five secoiridoids achieved superior results. MJN, JSM, IJM, and JMD showed higher affinities towards the Mpro target compared to the co-crystallized antagonist. Furthermore, the most active complexes (MJN, JSM, IJM, and JMD-Mpro) were subjected to MD simulations run for 150 ns and MM-GBSA calculations, compared to the co-crystallized inhibitor (O6K-Mpro). Finally, the SAR study clarified that JMD achieved the best anti-SARS-CoV-2 Mpro activity followed by MJN.Communicated by Ramaswamy H. Sarma.

The objective of this research was to create stable nickel nanoparticles using nickel chloride salt and a Schiff base ligand called DPMN. The synthesis process involved a two-step phase transfer procedure. Spectroscopic techniques such as UV-Visible and FT-IR were used to confirm the formation of ligand-stabilized nickel nanoparticles (DPMN-NiNPs). To analyze the size, surface morphology, and quality of DPMN-NiNPs, SEM and TEM techniques were utilized. In vitro studies were performed to investigate the potential anticancer activity of the synthesized compounds against three different cancer cell lines and one normal cell line, and the results were compared to those of cis-platin. The researchers also conducted tests to determine the ability of DPMN-NiNPs to bind to CT-DNA using various techniques such as electronic absorption, fluorescence, viscometric, and cyclic voltammetric. The results showed that the synthesized DPMN-NiNPs exhibited good DNA binding ability, which was further validated by denaturation of DNA using thermal and sonochemical methods. The researchers also investigated the antimicrobial and antioxidant activities of DPMN-NiNPs, which demonstrated better biological activities than DPMN alone. Furthermore, the synthesized nano compounds were found to selectively damage cancer cell lines without harming normal cell lines. Finally, the researchers examined the potential of DPMN-NiNPs as a catalyst in dye degradation by testing its ability to decompose methyl red dye using UV-Visible spectroscopy.Communicated by Ramaswamy H. Sarma.

Xiaoyao san (XYS) plays an important role in treatment of non-alcoholic fatty liver disease (NAFLD) with liver stagnation and spleen deficiency, but its specific mechanism is still unclear. This study aimed to investigate the material basis and mechanism by means of network pharmacology, metabolomics, systems biology and molecular docking methods. On this basis, NAFLD rat model with liver stagnation and spleen deficiency was constructed and XYS was used to intervene, and liver histopathology, biochemical detection, enzyme-linked immunosorbent assay, quantitative PCR assay and western blotting were used to further verify the mechanism. Through the above research methods, network pharmacology study showed that there were 94 targets in total for XYS in the treatment of NAFLD. Metabolomics study showed that NAFLD with liver depression and spleen deficiency had a total of 73 differential metabolites. Systems biology found that PTGS2 and PPARG were the core targets; Quercetin, kaempferol, naringenin, beta-sitosterol and stigmasterol were the core active components; AA, cAMP were the core metabolites. And molecular docking showed that the core active components can act well on the key targets. Animal experiments showed that XYS could improve liver histopathology, increase 5HT and NA, decrease INS and FBG, improve blood lipids and liver function, decrease AA, increase cAMP, down-regulate PTGS2, up-regulate PPARG, and decrease PGE2 and 15d-PGJ2. In conclusion, XYS might treat NAFLD with liver depression and spleen deficiency by down-regulating PTGS2, up-regulating PPARG, reducing AA content, increasing cAMP, improving insulin resistance, affecting glucose and lipid metabolism, inhibiting oxidative stress and inflammatory response.Communicated by Ramaswamy H. Sarma.

Herein, eight new NHC-based selenourea derivatives were synthesized and characterized by using spectroscopic method (1H, 19F, and 13C NMR, FT-IR), and elemental analysis techniques. These compounds were synthesized by mixing benzimidazolium salts, potassium carbonate, and selenium powder in ethyl alcohol. Additionally, the molecular and crystal structures of the three compounds (1c, 2b, and 2c) were determined using the single-crystal x-ray diffraction (XRD) method. Diffraction analysis demonstrated the partial carbon-selenium double-bond character of these compounds. All compounds were determined to be highly potent inhibitors for AChE and XO enzymes. The IC50 values for the compounds were found in the range of 0.361-0.754 μM for XO and from 0.995 to 1.746 μM for AChE. The DNA binding properties of the compounds were investigated. These compounds did not have a remarkable DNA binding property. Also, DPPH radical scavenging activities of the compounds were also investigated. Compounds (1c), (2a), (3a), and (3b) exhibited more pronounced DPPH radical scavenging activity when compared to other compounds. Docking studies were applied by using AutoDock 4 to determine interaction mechanism of the selected compounds (1a), (1b), and (3b). The compound (1b) has good binding affinity (-9.78 kcal/mol) against AChE, and (-6.86 kcal/mol) for XO target. Drug similarity properties of these compounds compared to positive controls were estimated and evaluated by ADMET analysis. Furthermore, molecular dynamics simulations have been applied to understand the accuracy of docking studies. These findings and the defined compounds could be potential candidates for the discovery and progress of effective medicine(s) for AChE and XO in the future.Communicated by Ramaswamy H. Sarma.

SP6 RNA polymerase (SP6 RNAP) is an essential enzyme for the transcription process in SP6 bacteriophage. SP6 RNAP plays a vital role in mRNA vaccine designing technology and other translational biotechnology research due to the high specificity towards its promoter. The self-replicating performance also put this polymerase to study extensively. Despite of the reports emphasizing the function of this enzyme, a detailed structural and functional understanding of RNA polymerase is not reported so far. Here, we report the first-ever information about SP6RNAP structure and its effect on promoter binding at different pH environments using molecular docking and molecular dynamics simulation (MDS) study. We also report the changes in polymerase conformations in different pH conditions using in-silico approach. The docking study was also performed for SP6 RNAP with SP6 promoter at different pH environments using the in-silico docking tools and conducted the MDS study for complexes. MM/PBSA and per residue energy contribution has been performed at three different pH environments. The structural aspects confirmed that the pH 7.9 state favors the polymerase functional activity in the transcription process which was in the range reported using transcription assay. This polymerase's unique features may play its emerging role as an efficient transcription factor in translational biological research.Communicated by Ramaswamy H. Sarma.

Cervical cancer (CC) is a global threat to women and our knowledge is frighteningly little about its underlying genomic contributors. Our research aimed to understand the underlying molecular and genetic mechanisms of CC by integrating bioinformatics and network-based study. Transcriptomic analyses of three microarray datasets identified 218 common differentially expressed genes (DEGs) within control samples and CC specimens. KEGG pathway analysis revealed pathways in cell cycle, drug metabolism, DNA replication and the significant GO terms were cornification, proteolysis, cell division and DNA replication. Protein-protein interaction (PPI) network analysis identified 20 hub genes and survival analyses validated CDC45, MCM2, PCNA and TOP2A as CC biomarkers. Subsequently, 10 transcriptional factors (TFs) and 10 post-transcriptional regulators were detected through TFs-DEGs and miRNAs-DEGs regulatory network assessment. Finally, the CC biomarkers were subjected to a drug-gene relationship analysis to find the best target inhibitors. Standard cheminformatics method including in silico ADMET and molecular docking study substantiated PD0325901 and Selumetinib as the most potent candidate-drug for CC treatment. Overall, this meticulous study holds promises for further in vitro and in vivo research on CC diagnosis, prognosis and therapies.Communicated by Ramaswamy H. Sarma.

The Bromodomain (BRD4) and extra-terminal (BET) protein family are reversible; lysine-acetylated epigenetic readers identified as key important epigenetic regulators for protein recognition in posttranslational modifications for targeting cancer for its role in super-enhancers and transcription of oncogene expression in cancer and other forms of cancer and various diseases. Firstly, JQ-1a small potent BET inhibitors, targeting BET proteins were currently in clinical trials to ablate cancer. The identified compounds were taken from the library of preexisting therapeutically potent molecules. The objective of the present study is to identify the potential small molecule inhibitors against BRD4 through in-silico approach for the treatment of cancer. In present study, designed an in-silico screening of small molecules through ligand-based pharmacophore studies against bromodomain-containing protein 4 (BRD-4) protein and used for virtual screening through Database and their binding affinity and interaction of identified molecules were predicted through molecular docking, molecular dynamics simulations for 12 fixed time period, Molecular mechanics (MMGBSA) binding free energy calculations, ADME with drug-likeness properties including violations of lipinski's rule of 5, Jorgensens rule of 3 and other parameters were studied. The docking results indicate from the reported database screened molecules were validated with docking score -7.92 to -4.27Kcal/mol for BRD4-BD1 and the best model identified 21 hits. Among these two drugs were filtered and scrutinized for their ability based on binding modes and common interaction, MMGBSA of the highest affinity -54.53 Kcal/mol of BRD4-BD1 and ADME properties of selected molecules were predicted for its various parameters, dynamics studies evaluating its binding stability using Maestro software. In Conclusion, two BRD4 inhibitors were found to bind strongly in the similar binding sites as JQ-1, highlighting the role of BRD4-BD1. These compounds were identified as promising new options for regulating epigenetics and understanding the structural needs of BRD4 protein, further research in these areas could lead to the development of more effective and targeted cancer drugs.Communicated by Ramaswamy H. Sarma.

Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers. In spite of great advances, treatment of the disease is a medical challenge. Epidermal-growth factor receptor (EGFR) has been taken as a promising cell surface target to develop anti-NSCLC therapies. The main bottleneck to attain clinical efficacy with current EGFR tyrosine kinase inhibitors (EGFR-TKIs) is the rapid spread of oncogenic mutations. Numerous efforts have been made for the synthesis of diverse EGFR-TKIs against resistance-conferring mutations. One of the best strategies to design potent agents would be to explore existing anti-NSCLC drugs at the nonclinical development stage and prioritize privileged structural patterns. Within current study, conformational stability of clinically frequent EGFR mutants (G719S, T790M, L858R and a double mutant form L858R/T790M) were validated via DynaMut and missense3D computational servers. Subsequently, structure activity relationship (SAR) and scaffold similarity inquiry were used to rationally propose a few erlotinib analogues. Intended molecules were subjected to molecular docking and top-scored binders were further analyzed through 50-ns all atom molecular dynamics (MD) simulations to infer the dynamic behavior. The aim was to offer potential binders to overwhelm clinically frequent EGFR-TK mutants. The linear interaction energy (LIE) method was applied to compute the binding free energies between EGFR and intended ligands. For this purpose, MD-based conformational sampling of ligand-enzyme complexes and ligand-water associations were used to acquire thermodynamic energy averages. Though mechanistic details are to be explored, results of the current study identify synthetically accessible quinazoline small molecules with potential affinity toward frequent EGFR-TK mutants.Communicated by Ramaswamy H. Sarma.