Luminescent iridium(III) dipyrrinato complexes: synthesis, X-ray structures, and DFT and photocytotoxicity studies of glycosylated derivatives.

A series of luminescent Ir(III) dipyrrinato complexes were synthesized having various aromatic chromophores at the C-5 position of dipyrrin ligands. The presence of different chromophores on the Ir(III) dipyrrinato complexes altered their optical properties and produced strong emission in the red to NIR region (680-900 nm) with huge Stokes shifts (5910-7045 cm-1). TD-DFT studies indicated significant charge distribution between dipyrrin ligands and Ir-cyclometalated units in all the molecules. X-ray crystal structures revealed an octahedral geometry of the Ir(III) center in the complex. The in vitro studies of the glycosylated Ir(III) complexes revealed strong photoluminescence with maximum Stokes shifts, and they showed significant photocytotoxicity in skin keratinocyte (HaCaT) and lung adenocarcinoma (A549) cells. The singlet oxygen generation quantum yields of glycosylated Ir(III) complexes were in the range of 70-78% in water. The estimated IC50 values were between 17 and 25 µM after light exposure, and confocal microscopy revealed significant localization of the glycosylated Ir(III) complexes in the endoplasmic reticulum (ER) of cancer cells. The neutral Ir(III) dipyrrinato complexes are promising tracking agents for cellular imaging in the biological window and for photodynamic therapy (PDT) applications.

DFT/TD-DFT study to decipher the fluoride induced ring opening process of spiropyran.

DFT/TD-DFT methods were used to determine the fluoride anion sensing mechanism of 3',6'-Bis(tert-butyldimethylsilyloxy)spiro[benzo[f]chromene3,9'ffuorene], abbreviated as SP. The description of ring opening in the ground state of SP molecule and its isomerization in open form is presented. It was revealed from the study that in the ground state, SP is the most stable form in contrast with the isomer obtained in the open form. To initiate the ring opening, at first, the fluoride ion attacks as a nucleophile to de-silylate the SP molecule. This attack of fluoride ion may induce Cspiro-O bond cleavage leading to the formation of two anionic species, i.e., MC-D1 and MC-D2 respectively (MC is merocyanin). The mono-de-silylation process was endogenic, which was followed by the ring opening process. Furthermore, the orthogonal geometry of probe SP does not show ICT character, whereas, MC-D1 and MC-D2 displayed ICT character owing to the formation of planar geometry along with an increase in conjugation. The fluorescence property of SP, and most stable isomers of open form (CT, MC-D1, and MC-D2) were predicted theoretically. The calculated emission spectra uncovered that SP may show fluorescence, which could be quenched in presence of fluoride anion.

In vitro and In silico Evaluation of Structurally Diverse Benzyl-pyrrolidine-3-ol Analogues as Apoptotic Agents via Caspase Activation.

The activation of caspases is central to apoptotic process in living systems. Defects in apoptosis have been implicated with carcinogenesis. Need to develop smart agents capable of inducing apoptosis in tumor cells is obvious. With this motive, diversity oriented synthesis of 1-benzylpyrrolidin-3-ol analogues was envisaged. The multi component Ugi reaction synthesized library of electronically diverse analogues was explored for cytotoxic propensity towards a panel of human cancer cell lines at 10 µM. The lead compounds exhibit a selective cytotoxicity towards HL-60 cells as compared to cell lines derived from solid tumors. Besides, their milder cytotoxic effect on non-cancerous cell lines reaffirm their selective action towards cancer cells only. The lead molecules were tested for their ability to target caspase-3, as a vital protease triggering apoptosis. The lead compounds were observed to induce apoptosis in HL-60 cells around 10 µM concentration. The lead compounds exhibited various non-covalent supra type interactions with caspase-3 key residues around the active site. The binding ability of lead compounds with caspase-3 was studied via molecular docking and molecular dynamic (MD) simulations. MD simulations indicated the stability of compound-caspase-3 complex throughout the 50 ns simulation run. The stability and bio-availability of the lead compounds under physiological conditions was assessed by their interaction with Bovine Serum Albumin (BSA) as model protein. BSA interactions of lead compounds were studied by various bio-physical methods and further substantiated with in silico MD simulations.

Identification of natural compound inhibitors against PfDXR: A hybrid structure-based molecular modeling approach and molecular dynamics simulation studies.

In the present contribution, multicomplex-based pharmacophore studies were carried out on the structural proteome of Plasmodium falciparum 1-deoxy-D-xylulose-5-phosphate reductoisomerase. Among the constructed models, a representative model with complementary features, accountable for the inhibition was used as a primary filter for the screening of database molecules. Auxiliary evaluations of the screened molecules were performed via drug-likeness and molecular docking studies. Subsequently, the stability of the docked inhibitors was envisioned by molecular dynamics simulations, principle component analysis, and molecular mechanics-Poisson-Boltzmann surface area-based free binding energy calculations. The stability assessment of the hits was done by comparing with the reference (beta-substituted fosmidomycin analog, LC5) to prioritize more potent candidates. All the complexes showed stable dynamic behavior while three of them displayed higher binding free energy compared with the reference. The work resulted in the identification of the compounds with diverse scaffolds, which could be used as initial leads for the design of novel PfDXR inhibitors.

Multicomplex-based pharmacophore modeling in conjunction with multi-target docking and molecular dynamics simulations for the identification of PfDHFR inhibitors.

Plasmodium falciparum dihydrofolate reductase enzyme (PfDHFR) is counted as one of the attractive and validated antimalarial drug targets. However, the point mutations in the active site of wild-type PfDHFR have developed resistance against the well-known antifolates. Therefore, there is a dire need for the development of inhibitors that can inhibit both wild-type and mutant-type DHFR enzyme. In the present contribution, we have constructed the common feature pharmacophore models from the available PfDHFR. A representative hypothesis was prioritized and then employed for the screening of natural product library to search for the molecules with complementary features responsible for the inhibition. The screened candidates were processed via drug-likeness filters and molecular docking studies. The docking was carried out on the wild-type PfDHFR (3QGT); double-mutant PfDHFR (3UM5 and 1J3J) and quadruple-mutant PfDHFR (1J3K) enzymes. A total of eight common hits were obtained from the docking calculations that could be the potential inhibitors for both wild and mutant type DHFR enzymes. Eventually, the stability of these candidates with the selected proteins was evaluated via molecular dynamics simulations. Except for SPECS14, all the prioritized candidates were found to be stable throughout the simulation run. Overall, the strategy employed in the present work resulted in the retrieval of seven candidates that may show inhibitory activity against PfDHFR and could be further exploited as a scaffold to develop novel antimalarials. Communicated by Ramaswamy H. Sarma.

In search of the representative pharmacophore hypotheses of the enzymatic proteome of Plasmodium falciparum: a multicomplex-based approach.

Drug resistance has made malaria an untreatable disease and therefore intensified the need for the development of new drugs and the identification of potential drug targets. In this pursuit, in silico efforts made in the past have not shown significant responses. Therefore, in the present work, the multicomplex-based pharmacophore modeling approach was employed to construct the pharmacophores of the 16 selected Plasmodium falciparum (Pf) targets. All the constructed hypotheses (153) were screened against a focused dataset made up of experimental actives of the chosen targets (3705 inhibitors). The rationale was to check the affinity of the inhibitors for the off-targets. Subsequently, the constructed hypotheses from each target were pooled based on the feature types and the pooled-hypotheses were then clustered to offer an insight about the pharmacophore similarity. Tanimoto similarity index was also calculated to look for the similarity among the inhibitors belonging to different Pf targets. Overall, the work was accomplished to bid healthier perceptive of the pharmacophore-based virtual screening and abet in providing guiding principles for the construction of stringent pharmacophores that can be employed for the screening.

Synthesis and photophysical studies on 2­styryl phenanthro[9,10­d]oxazole derivatives.

A new series of 2­styryl phenanthro[9,10­d]oxazoles was readily accessible from the condensation reaction of 9,10­phenanthroquinone with cinnamaldehydes in the presence of lactic acid. All these styryl dyes were isolated in good yields and characterized by various analytical and spectroscopic techniques. One of the dyes containing NO2 group (3d) was structurally characterized by single crystal X-ray analysis. These dyes displayed emission in blue to green region with larger Stokes shift values characteristic to the nature of substituents. In addition, positive solvatochromic trend was observed by increasing the solvent polarity suggestive of a more stabilized polar excited state. Moreover, the addition of trifluoroacetic acid leads to a prominent blue-shift in visible and emission color changes owing to the protonation of the nitrogen atom of oxazole moiety. Among the all, the oxazole derivative having NMe2 group (3b) exhibits good response to acidic pH in the range of 3.0 to 5.6 with a good linearity upon decreasing the pH from 8.0 to 2.16. The absorption studies were further supported by density functional theory calculations.

Identification of PfENR inhibitors: A hybrid structure-based approach in conjunction with molecular dynamics simulations.

In the current study, we have constructed receptor-based pharmacophore models by exploiting the Plasmodium falciparum enoyl-acyl carrier protein reductase (PfENR) structural proteome. The derived models were subjected to a series of validation procedures to list the representative hypotheses that can be used for the screening of the Drug-like Diverse Database. A set of 739 molecules was retrieved and analyzed for the adsorption, distribution, metabolism, excretion and toxicity (ADMET) and drug-likeness attributes. The filtered drug-like molecules (64) were then subjected to molecular docking and HYDE assessment studies. The hybrid structure-based approach yielded 4 molecules, UKR1308259, ENA1096786, UKR403454, and ASI51224, as PfENR inhibitors. The stability of these inhibitors was assessed using molecular mechanics-generalized born surface area approach-based free binding energy calculations and molecular dynamics simulations. Molecular mechanics-generalized born surface area calculations and molecular dynamics simulations showed that UKR1308259, ENA1096786, and ASI51224 were more potent PfENR inhibitors. The rationale behind the current work was to identify orally available inhibitor molecules with diverse scaffolds that could serve as initial leads for the drug design against PfENR.

Identification of InhA inhibitors: A combination of virtual screening, molecular dynamics simulations and quantum chemical studies.

In the present work, multiple pharmacophore-based virtual screening of the SPECS natural product database was carried out to identify novel inhibitors of the validated biological target, InhA. The pharmacophore models were built from the five different groups of the co-crystallized ligands present within the active site. The generated models with the same features from each group were pooled and subjected to the test set validation, receiver-operator characteristic analysis and Güner-Henry studies. A set of five hypotheses with sensitivity > 0.5, specificity > 0.5, area under curve (AUC) > 0.7, and goodness of hit score > 0.7 were retrieved and exploited for the virtual screening. The common hits (87 molecules) obtained from these hypotheses were processed via drug-likeness filters. The filtered molecules (27 molecules) were compared for the binding modes and the top scored molecules (12 molecules) along with the reference (triclosan (TCL), docking score = -11.65 kcal/mol) were rescored and reprioritized via molecular mechanics-generalized Born surface area approach. Eventually, the stability of reprioritized (10 molecules) docked complexes was scrutinized via molecular dynamics simulations. Moreover, the quantum chemical studies of the dynamically stable compounds (9 molecules) were performed to understand structural features essential for the activity. Overall, the protocol resulted in the recognition of nine lead compounds that can be targeted against InhA.

Prioritization of natural compounds against mycobacterium tuberculosis 3-dehydroquinate dehydratase: A combined in-silico and in-vitro study.

Enormous efforts have been endeavored to develop inhibitors against the potential therapeutic target, mycobacterium tuberculosis 3-dehydroquinate dehydratase (MtbDHQase) to combat resistance. Over a dozen of small molecules have been crystallized to characterize the structural basis of the inhibition. However, the studies accomplished so far, have not incorporated all the essential interactions of these complexes simultaneously, to identify the novel inhibitors. Therefore, an attempt was made to construct the pharmacophore models and identify the essential features that can be employed to prioritize the molecules against this target. Based on validation and expertise, we have identified such complimentary features from the natural compounds that can be used as initial hits. Subsequently, these hits were tested for their inhibitory roles in reducing the mycobacterium tuberculosis (Mtb) culture growth. Moreover, the docking simulations were performed to seek the possible interactions accountable for the activity of these candidates against MtbDHQase.

Identification of Mycobacterium tuberculosis enoyl-acyl carrier protein reductase inhibitors: A combined in-silico and in-vitro analysis.

Mycobacterium tuberculosis (Mtb), had developed evolutionary changes in its genome to adapt for survival and thereby generated multi-drug resistant strains. However, novel drug targets that remained unchanged for their biochemical role has impressed the research community to target such proteins. The comprehensive analysis of multiple protein targets has influenced us to make a consensus structural rule exploited by pharmacophore and other allied techniques from a large repository of protein structures. In this pursuit, we made a retrospective analysis of pharmacophores mapped from the tuberculosis structural proteome and identified unique patterns that can be employed for the novel molecules design. The current work on NADH-dependent enoyl-acyl carrier protein reductase (InhA) has yielded top scored pharmacophore models which were searched over SPECS natural product database to prioritize the molecules that can be targeted against Mtb. With efforts on rigorous validation and expertise, we have identified such pharmacophoric patterns from natural compounds that can be used as initial hits. Subsequently, these hits were subjected to in-vitro antitubercular evaluation to ensure the inhibitory activity against the mycobacterium culture growth (MtbH37Rv). Furthermore, docking simulations were carried out to provide an insight on the possible modes of interaction between the experimentally explored compounds and InhA.

Multicomplex-based pharmacophore modeling coupled with molecular dynamics simulations: An efficient strategy for the identification of novel inhibitors of PfDHODH.

Enormous efforts have been made in the past to identify novel scaffolds against the potential therapeutic target, Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH). Fourteen different organic molecules have been crystallized to understand the structural basis of the inhibition. However, the pharmacophoric studies carried out so far, have not exploited all the structural information simultaneously to identify the novel inhibitors. Therefore, an attempt was made to construct the pharmacophore hypotheses from the available PfDHODH structural proteome. Among the generated hypotheses, a representative hypothesis was employed as a primary filter to list the molecules with complimentary features accountable for inhibition. Moreover, the auxiliary evaluations of the filtered molecules were accomplished via docking and drug-likeness studies. Subsequently, the stability of the protein-ligand complex was evaluated by using molecular dynamics simulations (MDs). The molecular details of binding interactions of the potential hits were compared with the highly active experimental structure (5FI8) to seek the more potent candidates that can be targeted against PfDHODH. Overall, the combination of screening and stability procedures resulted in the identification of three potent candidates. The drug-likeness of these molecules lie within the acceptable range and consequently increased the opportunities for their development to new anti-malarials.

Structural Investigation of Vinca Domain Tubulin Binders by Pharmacophore, Atom based QSAR, Docking and Molecular Dynamics Simulations.

AIM AND OBJECTIVE: Vinca domain of tubulin protein is the potential target for different microtubule targeting drugs (MTD). However, its binding mechanism and structure-activityrelationship (SAR) is not well understood in terms of ligand-receptor interactions and structure functionality requirements. This limits the exploitation of vinca domain for developing novel clinical leads. Herein, as a progressive step towards the exploration of this target, we rendered the in-silico insight through the development of a robust pharmacophore model followed by the QSAR, Molecular Docking and Molecular Dynamics (MD) simulations. Furthermore, the study was undertaken to identify potent inhibitors that can inhibit vinca domain of tubulin. MATERIALS AND METHODS: Utilizing the well-defined tubulin polymerization inhibition activities, common pharmacophore hypotheses were constructed and scored for their rankings. The hypotheses were validated by 3D-Atom based QSAR and tested for various statistically relevant metrices. Thereafter, virtual screening was performed with ZINC natural product database and the screened hits were evaluated for structure-based studies via molecular docking and molecular dynamics simulations. RESULTS: The predictive 3D-QSAR based pharmacophore model consists of two hydrogen bond acceptors (A), two hydrogen bond donors (D) and one hydrophobic (H) group. Significance of the model was reflected from the statistical parameters viz. r2 = 0.98, q2 = 0.72, F = 562.9, RMSE = 0.11 and Pearson-R = 0.87. Further, the docking scores of the retrieved hits deciphered that the ligands were adequately bound in the pocket. Moreover, RMSD fluctuations of protein (1.0 to 1.75A) and ligand (0.3 to 2.3 Å) in molecular dynamics simulations insinuate towards the conformational and interactions stability of the complexes. CONCLUSION: The quantitative pharmacophore model was developed from range of natural product scaffolds in order to incorporate all the complimentary features accountable for inhibition. The obtained hits were found to occupy similar binding region and superimpose well over the reference ligand. Therefore, it can be concluded that hierarchical combination of methods exploited in this study can steer the identification of novel scaffolds. Moreover, the rendered hit molecules could serve as potential inhibitory leads for the development of improved inhibitors targeting Vinca domain.

First protein drug target's appraisal of lead-likeness descriptors to unfold the intervening chemical space.

Despite the advances in combinatorial chemistry, high throughput and virtual screening experiments, plethora of clinical studies disquiet due to lead and drug-likeness attritions. For mitigation, the knowledge of physicochemical properties are really useful for guiding and selection of compounds from libraries dictated by certain rule of thumbs. However, robust bio-technological and instrumental innovations have created exponential increase in novel compounds and databases which compelled rethinking of the evaluation procedures. Known descriptive molecular property filters proposed by Lipinski, Verber and Hann are not efficient enough to encompass long array of compounds. Moreover, these filters do not take into account the specificity of biological target. In this pursuit, we have tried to appraise eight molecular properties for two major classes of biological targets viz membrane proteins and ion channels binding ligands. These molecular properties were utilized to search for the specific attributes that can be identified as an intervening space for dictating the biological activity.

Synthesis, Structure, and Optical Studies of Donor-Acceptor-Type Near-Infrared (NIR) Aza-Boron-Dipyrromethene (BODIPY) Dyes.

Six donor-acceptor-type near-infrared (NIR) aza-boron-dipyrromethene (BODIPY) dyes and their corresponding aza-dipyrrins were designed and synthesized. The donor moieties at the 1,7-positions of the aza-BODIPY core were varied from naphthyl to N-phenylcarbazole to N-butylcarbazole. The 3,5-positions were also substituted with phenyl or thienyl groups in the aza-BODIPYs. Photophysical, electrochemical, and computational studies were carried out. The absorption and emission spectra of aza-BODIPYs were significantly redshifted (≈100 nm) relative to the parent tetraphenylaza-BODIPY. Fluorescence studies suggested effective energy transfer (up to 93 %) from donor groups to the aza-BODIPY core in all of the compounds under study. Time-dependent (TD)-DFT studies indicated effective electronic interactions between energy donor groups and aza-dipyrrin unit in all the aza-BODIPYs studied. The HOMO-LUMO gap (ΔE) calculated from cyclic voltammetry data was found to be lower for six aza-BODIPYs relative to their corresponding aza-dipyrrins.

Bridged bis-BODIPYs: their synthesis, structures and properties.

A series of bis-BODIPYs 1-6 bridged via thiophene, furan, N-alkylcarbazole, triphenyl-amine, para- and meta-phenylene groups have been synthesized and characterized by various spectroscopic techniques. The change in the spectroscopic properties of bis-BODIPYs upon varying the size of spacers was studied. X-ray crystal structures of three bis-BODIPYs containing triphenylamine, para- and meta-phenylene bridges were solved. Intermolecular C(H)π and ππ stacking interactions were observed in solid state structures of three bis-BODIPYs. The dihedral angles between the spacer unit and two boron-dipyrrin units were lower in all three compounds as compared to their corresponding monomers. This suggests increased interactions between the two boron-dipyrrin units in molecules which are in turn reflected in the anodic shifts in their reduction potentials. DFT studies indicated effective electronic interactions between spacers and two boron dipyrrin units in all the bis-BODIPYs. The calculated HOMO-LUMO gap was found to be lower for bis-BODIPY having bulky carbazole spacers and higher for bis-BODIPY having smaller furan spacers. Changing the spacer size clearly affected the spectroscopic properties of the bis-BODIPYs and red shifted absorption and emission maxima were observed for bis-BODIPYs with furan and thiophene spacers as compared to bis-BODIPYs with phenylene or bulky aromatic spacers.