Screening of potential phytomolecules against MurG as drug target in nosocomial pathogen Pseudomonas aeruginosa: perceptions from computational campaign.

The nosocomial infection outbreak caused by Pseudomonas aeruginosa remains a public health concern. Multi-drug resistant (MDR) strains of P. aeruginosa are rapidly spreading leading to a huge mortality rate because of the unavailability of promising antimicrobials. MurG glycotransferase [UDP-N-acetylglucosamine-N-acetylmuramyl (pentapeptide) pyrophosphoryl-undecaprenol N-acetylglucosamine transferase] is located at the plasma membrane and plays a key role in murein (peptidoglycan) biosynthesis in bacteria. Since MurG is required for bacterial cell wall synthesis and is non-homologous to Homo sapiens; it can be a potential target for the antagonist to treat P. aeruginosa infection. The discovery of high-resolution crystal structure of P. aeruginosa MurG offers an opportunity for the computational identification of its prospective inhibitors. Therefore, in the present study, the crystal structure of MurG (PDB ID: 3S2U) from P. aeruginosa was selected, and computational docking analyses were performed to search for functional inhibitors of MurG. IMPPAT (Indian medicinal plants, phytochemicals and therapeutic) phytomolecule database was screened by computational methods with MurG catalytic site. Docking results identified Theobromine (-8.881 kcal/mol), demethoxycurcumin (-8.850 kcal/mol), 2-alpha-hydroxycostic acid (-8.791 kcal/mol), aurantiamide (-8.779 kcal/mol) and petasiphenol (-8.685 kcal/mol) as a potential inhibitor of the MurG activity. Further, theobromine and demethoxycurcumin were subjected to MDS (molecular dynamics simulation) and free energy (MM/GBSA) analysis to comprehend the physiological state and structural stability of MurG-phytomolecules complexes. The outcomes suggested that these two phytomolecules could act as most favorable natural hit compounds for impeding the enzymatic action of MurG in P. aeruginosa, and thus it needs further validation by both in vitro and in vivo analysis. HIGHLIGHTSThe top phytomolecules such as theobromine, demethoxycurcumin, 2-alpha-hydroxycostic acid, aurantiamide and petasiphenol displayed promising binding with MurG catalytic domain.MurG complexed with theobromine and demethoxycurcumin showed the best interaction and stable by MD simulation at 100 ns.The outcome of MurG binding phytomolecules has expanded the possibility of hit phytomolecules validation.Communicated by Ramaswamy H. Sarma.

High throughput virtual screening and molecular dynamics simulation analysis of phytomolecules against BfmR of Acinetobacter baumannii: anti-virulent drug development campaign.

Acinetobacter baumannii is a notorious multidrug resistant bacterium responsible for several hospital acquired infections assisted by its capacity to develop biofilms. A. baumannii BfmR (RstA), a response regulator from the BfmR/S two-component signal transduction system, is the major controller of A. baumannii biofilm development and formation. As a result, BfmR represents a novel target for anti-biofilm treatment against A. baumannii. The discovery of the high-resolution crystal structure of BfmR provides a good chance for computational screening of its probable inhibitors. Therefore, in this study we aim to search new, less toxic, and natural BfmR inhibitors from 8450 phytomolecules available in the Indian Medicinal Plants, Phytochemistry and Therapeutic (IMPPAT) database by analyzing molecular docking against BfmR (PDB ID: 6BR7). Out of these 8450 phytomolecules 6742 molecules were successfully docked with BfmR with the docking score range -6.305 kcal/mol to +5.120 kcal/mol. Structure based-molecular docking (SB-MD) and ADMET (absorption, distribution, metabolism, excretion, & toxicity) profile examination revealed that Norepinephrine, Australine, Calystegine B3, 7,7 A-Diepialexine, and Alpha-Methylnoradrenaline phytocompounds strongly binds to the active site residues of BfmR. Furthermore, molecular dynamics simulation (MDS) studies for 100 ns and the binding free energy (MM/GBSA) analysis elucidated the binding mechanism of Calystegine B3, 7,7 A-Diepialexine, and Alpha-Methylnoradrenaline to BfmR. In summary, these phytocompounds seems to have the promising molecules against BfmR, and thus necessitates further verification by both in vitro and in vivo experiments. HighlightsBfmR plays a key role in biofilm development and exopolysaccharide (EPS) synthesis in A. baumannii.Computational approach to search for promising BfmR inhibitors from IMPAAT database.The lead phytomolecules such as Calystegine B3, 7,7 A-Diepialexine, and Alpha-Methylnoradrenaline displayed significant binding with BfmR active site.The outcome of BfmR binding phytomolecules has broadened the scope of hit molecules validation.Communicated by Ramaswamy H. Sarma.

Novel B, C-ring truncated deguelin derivatives reveals as potential inhibitors of cyclin D1 and cyclin E using molecular docking and molecular dynamic simulation.

The overexpression of cyclin D1 and cyclin E due to their oncogenic potential and amplification has been associated with a higher mortality rate in many cancers. The deguelin is a natural compound, has shown promising anti-cancer activity by directly binding cyclin D1 and cyclin E and thus suppressing its function. The C7a atomic position of deguelin structure contains a proton that generates stabilized radical, as a result, decomposed deguelin reduces its structural stability and significantly decreases its biological activity. To design deguelin derivatives with the reduced potential side effect, series of B, C-ring truncated derivatives were investigated as cyclin D1 and cyclin E inhibitors. R-group-based enumeration was implemented in the deguelin scaffold using the R-group enumeration module of Schrödinger. Drug-Like filters like, REOS and PAINs series were applied to the enumerated compound library to remove compounds containing reactive functional groups. Further, screened compounds were docked within the ligand-binding cavity of cyclin D1 and cyclin E crystal structure, using Glide SP and XP protocol to obtain docking poses. Enrichment calculations were done using SchrÖdinger software, with 1000 decoy compounds (from DUD.E database) and 60 compounds (XP best poses) along with deguelin, to validate the docking protocol. The receiver operating characteristic (ROC) curve indicates R2 = 0.94 for cyclin D1 and R2 = 0.79 for cyclin E, suggesting that the docking protocol is valid. Besides, we explored molecular dynamics simulation to probe the binding stability of deguelin and its derivatives within the binding cavity of cyclin D1 and cyclin E structures which are associated with the cyclin D1 and cyclin E inhibitory mechanism.

Synthesis, characterization, molecular docking and anti-tubercular activity of Plumbagin-Isoniazid Analog and its ß-cyclodextrin conjugate.

A novel Plumbagin-Isoniazid Analog (PLIHZ) and its ß-cyclodextrin inclusion complex (PLIHZCD) is prepared, characterized and evaluated for antitubercular activity under low and high iron conditions. PLIHZCD inclusion complex was characterized by Fourier Transform Infra-Red (FTIR), Differential Scanning Calorimetry (DSC), Powder X-ray Diffraction Studies (PXRD), (1)H NMR Studies and Scanning Electron Microscopic (SEM) analysis. The orientation and interaction of PLIHZ and CD was studied by molecular docking. PLIHZCD exhibited superior activity (MIC of 4 µg/ml) than PLIHZ and PL under 7H9 medium conditions. The standard anti-tubercular compound INH exhibited MIC values of 0.125 and 32 µg/ml under high and low iron conditions, whereas the conjugate PLIHZ exhibited MIC values of 0.5 and 2.0 µg/ml under high and low iron (corresponding to isoniazid resistant condition) indicating the advantage of combining plumbagin with INH overcoming resistance. The cyclodextrin conjugate offers improved aqueous solubility and thermal stability which are advantages in the treatment protocol.

Synthesis, characterization and anti-tumor activity of novel thymoquinone analogs against pancreatic cancer.

Thymoquinone (TQ), isolated from the seeds of Nigella sativa, show moderate efficacy against pancreatic cancer. In the present work we report synthesis and characterization of novel TQ analogs appended with gallate and fluorogallate pharmacophores and evaluation of their effects against pancreatic cancer cell lines for cell viability and induction of apoptosis. The efficacy of the analogs alone or in combination with Gemcitabine was assessed in vitro. LC-MS spectra of ATQTHB and ATQTFB showed major peaks corresponding to expected M+1 fragment at 316.34 and 322.34 respectively. Molecular docking studies revealed good fit for these analogs in the COX-2 protein cavity with better binding energies compared to parent TQ compound. Present TQ analogs exhibit superior anti-proliferative activity, excellent chemo-sensitizing activity against pancreatic cancer in vitro and in combination with Gemcitabine.

Novel dual cyclooxygenase and lipoxygenase inhibitors targeting hyaluronan-CD44v6 pathway and inducing cytotoxicity in colon cancer cells.

Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) enzyme have been found to play a role in promoting growth in colon cancer cell lines. The di-tert-butyl phenol class of compounds has been found to inhibit both COX-2 and 5-LOX enzymes with proven effectiveness in arresting tumor growth. In the present study, the structural analogs of 2,6 di-tert-butyl-p-benzoquinone (BQ) appended with hydrazide side chain were found to inhibit COX-2 and 5-LOX enzymes at micromolar concentrations. Molecular docking of the compounds into COX-2 and 5-LOX protein cavities indicated strong binding interactions supporting the observed cytototoxicities. The signaling interaction between endogenous hyaluronan and CD44 has been shown to regulate COX-2 activities through ErbB2 receptor tyrosine kinase (RTK) activation. In the present studies it has been observed for the first time, that three of our COX/5-LOX dual inhibitors inhibit proliferation upon hydrazide substitution and prevent the activity of pro-angiogenic factors in HCA-7, HT-29, Apc10.1 cells as well as the hyaluronan synthase-2 (Has2) enzyme over-expressed in colon cancer cells, through inhibition of the hyaluronan/CD44v6 cell survival pathway. Since there is a substantial enhancement in the antiproliferative activities of these compounds upon hydrazide substitution, the present work opens up new opportunities for evolving novel active compounds of BQ series for inhibiting colon cancer.

Novel Aza-resveratrol analogs: synthesis, characterization and anticancer activity against breast cancer cell lines.

Novel Aza-resveratrol analogs were synthesized, structurally characterized and evaluated for cytotoxic activity against MDA-MB-231 and T47D breast cancer cell lines, which exhibited superior inhibitory activity than parent resveratrol compound. The binding mechanism of these compounds with estrogen receptor-α was rationalized by molecular docking studies which indicated additional hydrogen binding interactions and tight binding in the protein cavity. Induction of Beclin-1 protein expression in breast cancer cell lines after treatment with newly synthesized resveratrol analogs indicated inhibition of growth of these cell lines through autophagy. The study highlighted the advantage of introducing the imino-linkage in resveratrol motif in enhancing the anticancer potential of resveratrol suggesting that these analogs can serve as better therapeutic agents against breast cancer and can provide starting point for building more potent analogs in future.

Synthesis, characterization, molecular docking and cytotoxic activity of novel plumbagin hydrazones against breast cancer cells.

Novel plumbagin hydrazonates were prepared, structurally characterized and evaluated for anti-proliferative activity against estrogen receptor-positive MCF-7 and triple negative MDA-MB-231 and MDA-MB-468 breast cancer cell lines which exhibited superior inhibitory activity than parent plumbagin compound. Molecular docking studies indicated that hydroxyl groups on plumbagin and hydrazonate side chain favor additional hydrogen bonding interactions with amino acid residues in p50-subunit of NF-κB protein and these compounds inhibited NF-κB expression which may be responsible for the enhanced anti-proliferative activity. These compounds were found to be more effective against triple negative breast cancer cells and might serve as a starting point for building future strategies against triple negative breast cancers which are known for their increased drug resistance and poor prognosis of breast cancer patients.

Synthesis and characterization of pyruvate-isoniazid analogs and their copper complexes as potential ICL inhibitors.

Currently used anti-tubercular drugs target actively growing Mycobacterium tuberculosis (Mtb) but there are no current therapies targeting persistent mycobacteria. Isocitrate lyase (ICL) is an important enzyme of the glyoxylate shunt pathway used by Mtb for sustaining intracellular infection in inflammatory macrophages under conditions of stress such as nutrient depletion and anaerobic metabolism. Since the humans do not possess this enzyme it constitutes an attractive target for selective drug design. Present work describes synthesis and structural characterization of pyruvate-isoniazid conjugates and their copper complexes with potent anti-tubercular activities against M. tuberculosis H37Rv.