New thiazolyl-isoxazole derivatives as potential anti-infective agents: design, synthesis, in vitro and in silico antimicrobial efficacy.

Antimicrobial resistance threatens the efficacious prevention and treatment of infectious diseases caused by microorganisms. To combat microbial infections, the need for new drug candidates is essential. In this context, the design, synthesis, antimicrobial screening, and in silico study of a new series of 5-aryl-3-(2-arylthiazol-4-yl)isoxazole (9a-t) have been reported. The structure of new compounds was confirmed by spectrometric methods. Compounds 9a-t were evaluated for in vitro antitubercular and antimicrobial activity. Against M. tuberculosis H37Rv, fourteen compounds showed good to excellent antitubercular activity with MIC 2.01-9.80 µM. Compounds 9a, 9b, and 9r showed four-fold more activity than the reference drug isoniazid. Nine compounds, 9a, 9b, 9d, 9e, 9i, 9q, 9r, 9s, and 9t, showed good antibacterial activity against E. coli with MIC 7.8-15.62 µg/mL. Against A. niger, four compounds showed good activity with MIC 31.25 µg/mL. Against C. albicans, all twenty compounds reported excellent to good activity with MIC 7.8-31.25 µg/mL. Compounds 9c-e, 9g-j, and 9q-t showed comparable activity concerning the reference drug fluconazole. The compounds 9a-t were screened for cytotoxicity against 3t3l1 cell lines and found to be less or non-cytotoxic. The in silico study exposed that these compounds displayed high affinity towards the M. tuberculosis targets PanK, DprE1, DHFR, PknA, KasA, and Pks13, and C. albicans targets NMT, CYP51, and CS. The compound 9r was evaluated for structural dynamics and molecular dynamics simulations. The potent antitubercular and antimicrobial activity of 5-aryl-3-(2-arylthiazol-4-yl)isoxazole (9a-t) derivatives has recommended that these compounds could assist in treating microbial infections.Communicated by Ramaswamy H. Sarma.

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

BACKGROUND: 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. OBJECTIVE: 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. RESULTS: 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. CONCLUSION: 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.

Synthesis, biological screening and in silico studies of new N-phenyl-4-(1,3-diaryl-1H-pyrazol-4-yl)thiazol-2-amine derivatives as potential antifungal and antitubercular agents.

A new series of N-aryl-4-(1,3-diaryl-1H-pyrazol-4-yl)thiazol-2-amine, (8a-x) have been synthesized by a cyclo-condensation reaction of 2-bromo-1-(1,3-diphenyl-1H-pyrazol-4-yl)ethanone (6a-f) with N-aryl thiourea, (7a-d). The structure of newly synthesized N-aryl-4-(1,3-diaryl-1H-pyrazol-4-yl)thiazol-2-amine, (8a-x) derivatives was analyzed by 1H NMR, 13C NMR and Mass spectral analysis. The compounds 8a-x were screened for in vitro antimicrobial activity against Escherichia coli, Proteus mirabilis, Bacillus subtilis, Staphylococcus aureus, Candida albicans and Aspergillus niger. and antitubercular activity against M. tuberculosis H37Rv strain. Among the twenty-four pyrazolyl-thiazole derivatives, six compounds 8a, 8b, 8j, 8n, 8o and 8s showed good activity against S. aureus. Against A. niger, all synthesized derivatives showed good antifungal activity. Fifteen pyrazolyl-thiazole derivatives 8a, 8f, 8g, 8h, 8j, 8k, 8n, 8o, 8p, 8q, 8r, 8s, 8t, 8w and 8x showed good antitubercular activity with MIC 1.80-7.34 µM (0.8-3.12 µg/mL), these derivatives have showed more activity than the drugs isoniazid and ethambutol. The active compounds were further screened for cytotoxicity activity against the mouse embryonic fibroblast cells (3t3l1) cell lines at 12.5 and 25 µg/mL concentrations and found less or non-cytotoxicity. To know the plausible mode of action, the synthesized pyrazolyl-thiazole derivatives were studied for pharmacokinetics, toxicity profiles and binding interactions along with an in-depth analysis of structural dynamics and integrity using prolonged molecular dynamics (MD) simulation. The compounds have shown significant docking scores in the range of -7.98 to -5.52 and -9.44 to -7.2 kcal/mol with the M. tuberculosis enoyl reductase (M. tb. InhA) and C. albicans sterol 14-α demethylase (C. ab. CYP51), respectively. Thus, the significant antifungal and antitubercular activity of N-aryl-4-(1,3-diaryl-1H-pyrazol-4-yl)thiazol-2-amine, (8a-x) derivatives incited that, these scaffolds could assist in the development of lead compounds to treat fungal and antitubercular infections.

Comprehensive computational study in the identification of novel potential cholesterol lowering agents targeting proprotein convertase subtilisin/kexin type 9.

The enzymatic target proprotein convertase subtilisin/kexin type 9 (PCSK9) is critically involved in the regulation of the lipoprotein metabolism leading to the degradation of low-density lipoprotein receptors (LDLRs) upon binding. Drugs that lower LDL cholesterol (LDL-C) through the inhibition of PCSK9 are useful in the management of hypercholesterolemia which greatly reduces the associated risk of atherosclerotic cardiovascular disease (CVD). In 2015, anti-PCSK9 monoclonal antibodies (mAbs), alirocumab and evolocumab were approved but owing to their high costs their prior authorization practices were impeded, reducing their long-term adherence. This has drawn considerable attention for the development of small-molecule PCSK9 inhibitors. In this research work, novel and diverse molecules with affinity towards PCSK9 thereby having ability to lower cholesterol. A hierarchical multistep docking was implemented to identify small molecules from chemical libraries with a score cutoff -8.00 kcal/mol, thereby weeding all the non-potential molecules. A set of seven representative molecules Z1139749023, Z1142698190, Z2242867634, Z2242893449, Z2242894417, Z2242909019, and Z2242914794 have been identified from a comprehensive computational study which included assessment of pharmacokinetics and toxicity profiles and binding interactions along with in-depth analysis of structural dynamics and integrity using prolong molecular dynamics (MD) simulation (in-duplicate). Furthermore the binding affinity of these PCSK9 inhibitory candidates molecules was ascertained over 1000 trajectory frames using MM-GBSA calculations. The molecules reported herein are propitious candidates for further development through necessary experimental considerations.Communicated by Ramaswamy H. Sarma.

Prediction of Ocular Toxicity of Potential Degradation Products of Proparacaine Hydrochloride Subjected under ICH Recommended Stress Conditions.

BACKGROUND: Proparacaine hydrochloric ophthalmic solution (0.5%) is widely used as ophthalmic anesthetic for short conjunctival and corneal procedures. In connection to this, present research work was conducted to investigate ocular toxicity of its probable degradation products (DPs), which were generated after treating drug with stressors mentioned under International Conference on Harmonization (ICH) guideline Q1A (R2). RESULT: The probable DPs were generated by placing drug under various stress conditions to generate similarity of the effect of stressor which drug supposed to face during its life cycle. The hydrolytic stress condition under acidic, basic and neutral environment formed two major DPs, while the drug was stable and did not generate any DP when subjected to oxidative, dry heat and photolytic stress. The separation of DPs was carried out using high performance liquid chromatographic system. The structural identification of DPs was carried out by subjecting degradation samples to liquid chromatography coupled with mass spectrometry. These DPs were screened using in-silico ocular toxicity prediction models Pub-SVM to predict their potential to cause irritation/corrosion to eye. CONCLUSIONS: The DPs identified were DP 1 (2-(diethyl amino) ethanol) and DP 2 (3-amino-4-propoxybenzoic acid). The in-silico ocular toxicity study predicted that DP 1 has potential of eye corrosion (EC) and eye irritation (EI), whereas DP 2 has a potential EI. The drug was found safe and devoid of any EC and EI potential.

Design, synthesis and molecular docking studies of new azomethine derivatives as promising anti-inflammatory agents.

Herein, we synthesized a series of Ibuprofen-based 4a-k, quinoxaline-based 9a-f and pyridine-based 13a-h azomethine derivatives and studied their anti-inflammatory potency. The in-silico docking studies of the synthesized compounds 4a-k revealed better affinity for COX-2 as compared to COX-1 with best binding exhibited by 4a, 4d, and 4k.In vitro COX-1 and COX-2 inhibition assay performed on the azomethine derivatives further proved that synthesized compounds of series 4, 9 and 13 showed less inhibition of COX-1 enzyme than that of COX-2 enzyme. However, their SI values indicated that compounds had no COX-2 selectivity. The in-vivo screening of the selected compounds indicated compound 4d to be more potent exhibiting the best % inhibition of 70.70 ± 2.41, as compared to the standard NSAIDs. Based on the above observations, a well defined structure activity relationship analysis (SAR) has been described showcasing the importance of various functionalities for anti-inflammatory effects. Further, the azomethine derivatives have been found to be better superoxide radical scavengers with no significant DPPH activity. Due to their antioxidant properties, compounds were screened for their cytotoxicity against cervical cancer derived HeLa and breast cancer derived MCF-7 cell with the drug Paclitaxel as the standard. However, no significant cytotoxic effect was observed for the compounds. Also, the late apoptosis in cervical HeLa cancer cells did not show the expected results, as the compounds proved to be weakly cytotoxic. Thus, the major findings of the work demonstrates the Schiff bases to be promising anti-inflammatory agents compatible with NSAIDs, having moderate anti-oxidant properties with minimal cytotoxicity.

The cocrystal of 3-((4-(3-isocyanobenzyl) piperazine-1-yl) methyl) benzonitrile with 5-hydroxy isophthalic acid prevents protofibril formation of serum albumin.

The formation of amyloid-like fibrils is a central problem in biophysical chemistry and medicine. Fibril formation and their deposition in various tissues and organs are associated with many human diseases. Searching for molecules able to prevent the formation of fibrils is, therefore, necessary. In this work, we examined the potential of a cocrystal (SS3) of 3-((4-(3-isocyanobenzyl) piperazine-1-yl) methy) benzonitrile with 5-hydroxy isophthalic acid, to prevent fibrillation of human serum albumin. We found that the cocrystal strongly bound to human serum albumin (HSA) with association constant (Ka) of 5.8 ± 0.7 × 105 M-1. The SS3 binding was found to cause small alterations in both secondary and tertiary structure of the protein. Transmission electron microscopy showed that the cocrystal completely prevented the formation of worm-like protofibrils by HSA at SS3/HSA molar ratio of 1:1. The molecule was found to prevent the aggregation in a concentration dependent manner. It was also observed that most of protein in the presence of SS3 remained in soluble state and the secondary structure contained native-like α-helical structure. Therefore, we conclude that the cocrystal effectively prevented conversion of HSA into worm-like protofibril. These finding suggest that combination of molecules in the form of cocrystal or other stable combination could pave a way for the development of drugs against amyloidosis.Communicated by Ramaswamy H. Sarma.

Assessment of elementary derivatives of 1,5-benzodiazepine as anticancer agents with synergy potential.

Herein, we designed and synthesized 1,5-benzodiazepines as a lead molecule for anticancer activity and as potent synergistic activity with drug Methotrexate. Working under the framework of green chemistry principles, series of 1,5-benzodiazepine derivatives (3a-3a1) were synthesized using biocatalyst i.e. thiamine hydrochloride under solvent free neat heat conditions. These compounds were screened for in vitro anti cancer activity against couple of cancer cell lines (HeLa and HEPG2) and normal human cell line HEK-293 via MTT assay. The IC50 values for the compounds were in the range 0.067 to 0.35 µM, better than Paclitaxel and compatible with the drug Methotrexate. Compound 3x was found to be influential against both the cell lines with IC50 values of 0.067 ± 0.002 µM against HeLa and 0.087 ± 0.003 µM against HEPG2 cell line, having activity as compatible to the standard drug Methotrexate. Bioinformatic analysis showed that these compounds are good tyrosine kinase inhibitors which was then proved using enzyme inhibition assay. The studies of apoptosis revealed late apoptotic mode of cell death for the compounds against HEPG2 cancer cell line using flow cytometry method. Synergistic studies of compound 3x and drug Methotrexate showed that the combination was highly active against cancer HeLa and HEPG2 cell line with IC50 value 0.046 ± 0.002 µM and 0.057 ± 0.002 µM respectively, which was well supported by apoptosis pathway. Further the compounds proved its scope as DNA intercalating agents, as its molecular docking and DNA binding studies revealed that the compounds would fit well into the DNA strands.

The reorganization of conformations, stability and aggregation of serum albumin isomers through the interaction of glycopeptide antibiotic teicoplanin: A thermodynamic and spectroscopy study.

The drugs-protein binding study is of growing importance for drug-repurposing against amyloidosis. In this work, we study the binding of teicoplanin (TPN), a glycopeptide antibiotic, with bovine serum albumin (BSA) in its neutral (N), physiological (P) and basic (B) forms, which exist at pH 6, pH 7.4 and pH 9, respectively. The binding and thermodynamic parameters of TPN binding were determined by isothermal titration calorimetry (ITC) and fluorescence quench titration methods. Two binding sites were observed for N and P forms, whereas B form showed only one binding site. ITC and molecular docking results indicated that TPN-BSA complex formation is stabilized by hydrogen bonds, salt bridges and hydrophobic interaction. The red-edge excitation shift (REES) study indicated an ordered compact and spatial arrangement of the TPN bound protein molecule. TPN was found to affect the secondary and tertiary structures of B form only. The TPN binding was observed to marginally stabilize BSA isomers. TPN was also found to inhibit BSA aggregation as monitored by Rayleigh light scattering and thioflavin T binding assay. The current in vitro study will open a new path to explore the possible use of TPN as potential drugs to treat amyloidosis.

Novel p-Functionalized Chromen-4-on-3-yl Chalcones Bearing Astonishing Boronic Acid Moiety as MDM2 Inhibitor: Synthesis, Cytotoxic Evaluation and Simulation Studies.

BACKGROUND: Novel 4-[3-(6/7/8-Substituted 4-Oxo-4H-chromen-3-yl)acryloyl]phenylboronic acid derivatives (5a-h) as well as other 6/7/8-substituted-3-(3-oxo-3-(4-substitutedphenyl) prop-1-enyl)-4H-chromen-4-one derivatives (3a-u) have been designed as p53-MDM2 pathway inhibitors and reported to possess significant cytotoxic properties against several cancer cell lines. OBJECTIVES: The current project aims to frame the structure-anticancer activity relationship of chromen-4-on-3-yl chalcones (3a-u/5a-h). In addition, docking studies were performed on these chromeno-chalcones in order to have an insight into their interaction possibilities with MDM2 protein. METHODS: Twenty-nine chromen-4-on-3-yl chalcone derivatives (3a-u/5a-h) were prepared by utilizing silica supported-HClO4 (green route with magnificent yield) and tested against four cancer cell lines (HCT116, MCF-7, THP-1, NCIH322). RESULTS: Among the series 3a-u, compound 3b exhibited the highest anticancer activity (with IC50 values ranging from 8.6 to 28.4 µM) overall against tested cancer cell lines. Interestingly, para- Boronic acid derivative (5b) showed selective inhibition against colon cancer cell line, HCT-116 with an IC50 value of 2.35 µM. Besides the emblematic hydrophobic interactions of MDM2 inhibitors, derivative 5b was found to exhibit extra hydrogen bonding with GLN59 and GLN72 residues of MDM2 in molecular dynamics (MD) simulation. All the compounds were virtually nontoxic against normal fibroblast cells. CONCLUSION: Novel compounds were obtained with good anticancer activity especially 6- Chlorochromen-4-one substituted boronic acid derivative 5b. The molecular docking study proposed good activity as a MDM-2 inhibitor suggesting hydrophobic as well as hydrogen bonding interactions with MDM2.

Characterization of pioglitazone cyclodextrin complexes: Molecular modeling to in vivo evaluation.

AIMS: The objective of present study was to study the influence of different ß-cyclodextrin derivatives and different methods of complexation on aqueous solubility and consequent translation in in vivo performance of Pioglitazone (PE). MATERIAL AND METHODS: Three cyclodextrins: ß-cyclodextrin (BCD), hydroxypropyl-ß-cyclodextrin (HPBCD) and Sulfobutylether-7-ß-cyclodextrin (SBEBCD) were employed in preparation of 1:1 Pioglitazone complexes by three methods viz. co-grinding, kneading and co-evaporation. Complexation was confirmed by phase solubility, proton NMR, Fourier Transform Infrared spectroscopy, Differential Scanning Calorimetry (DSC) and X-Ray diffraction (XRD). Mode of complexation was investigated by molecular dynamic studies. Pharmacodynamic study of blood glucose lowering activity of PE complexes was performed in Alloxan induced diabetic rat model. RESULTS: Aqueous solubility of PE was significantly improved in presence of cyclodextrin. Apparent solubility constants were observed to be 254.33 M(-1) for BCD-PE, 737.48 M(-1) for HPBCD-PE and 5959.06 M(-1) for SBEBCD-PE. The in silico predictions of mode of inclusion were in close agreement with the experimental proton NMR observation. DSC and XRD demonstrated complete amorphization of crystalline PE upon inclusion. All complexes exhibited >95% dissolution within 10 min compared to drug powder that showed <40% at the same time. Marked lowering of blood glucose was recorded for all complexes. CONCLUSION: Complexation of PE with different BCD significantly influenced its aqueous solubility, improved in vitro dissolution and consequently translated into enhanced pharmacodynamic activity in rats.

Physical basis for the ofloxacin-induced acceleration of lysozyme aggregation and polymorphism in amyloid fibrils.

Aggregation of globular proteins is an intractable problem which generally originates from partially folded structures. The partially folded structures first collapse non-specifically and then reorganize into amyloid-like fibrils via one or more oligomeric intermediates. The fibrils and their on/off pathway intermediates may be toxic to cells and form toxic deposits in different human organs. To understand the basis of origins of the aggregation diseases, it is vital to study in details the conformational properties of the amyloidogenic partially folded structures of the protein. In this work, we examined the effects of ofloxacin, a synthetic fluoroquinolone compound on the fibrillar aggregation of hen egg-white lysozyme. Using two aggregation conditions (4M GuHCl at pH 7.0 and 37 °C; and pH 1.7 at 65 °C) and a number of biophysical techniques, we illustrate that ofloxacin accelerates fibril formation of lysozyme by binding to partially folded structures and modulating their secondary, tertiary structures and surface hydrophobicity. We also demonstrate that Ofloxacin-induced fibrils show polymorphism of morphology, tinctorial properties and hydrophobic surface exposure. This study will assist in understanding the determinant of fibril formation and it also indicates that caution should be exercised in the use of ofloxacin in patients susceptible to various aggregation diseases.

Evaluation of risedronate as an antibiofilm agent.

Escherichia coli cra null mutants have been reported in the literature to be impaired in biofilm formation. To develop E. coli biofilm-inhibiting agents for prevention and control of adherent behaviour, analogues of a natural Cra ligand, fructose-1,6-bisphosphate, were identified based on two-dimensional similarity to the natural ligand. Of the analogues identified, those belonging to the bisphosphonate class of drug molecules were selected for study, as these are approved for clinical use in humans and their safety has been established. Computational and in vitro studies with purified Cra protein showed that risedronate sodium interacted with residues in the fructose-1,6-bisphosphate-binding site. Using a quantitative biofilm assay, risedronate sodium, at a concentration of 300-400 µM, was found to decrease E. coli and Salmonella pullorum biofilm formation by >60 %. Risedronate drastically reduced the adherence of E. coli cells to a rubber Foley urinary catheter, demonstrating its utility in preventing the formation of biofilm communities on medical implant surfaces. The use of risedronate, either alone or in combination with other agents, to prevent the formation of biofilms on surfaces is a novel finding that can easily be translated into practical applications.

In silico optimization of pharmacokinetic properties and receptor binding affinity simultaneously: a 'parallel progression approach to drug design' applied to ß-blockers.

The present work exploits the potential of in silico approaches for minimizing attrition of leads in the later stages of drug development. We propose a theoretical approach, wherein 'parallel' information is generated to simultaneously optimize the pharmacokinetics (PK) and pharmacodynamics (PD) of lead candidates. ß-blockers, though in use for many years, have suboptimal PKs; hence are an ideal test series for the 'parallel progression approach'. This approach utilizes molecular modeling tools viz. hologram quantitative structure activity relationships, homology modeling, docking, predictive metabolism, and toxicity models. Validated models have been developed for PK parameters such as volume of distribution (log Vd) and clearance (log Cl), which together influence the half-life (t1/2) of a drug. Simultaneously, models for PD in terms of inhibition constant pKi have been developed. Thus, PK and PD properties of ß-blockers were concurrently analyzed and after iterative cycling, modifications were proposed that lead to compounds with optimized PK and PD. We report some of the resultant re-engineered ß-blockers with improved half-lives and pKi values comparable with marketed ß-blockers. These were further analyzed by the docking studies to evaluate their binding poses. Finally, metabolic and toxicological assessment of these molecules was done through in silico methods. The strategy proposed herein has potential universal applicability, and can be used in any drug discovery scenario; provided that the data used is consistent in terms of experimental conditions, endpoints, and methods employed. Thus the 'parallel progression approach' helps to simultaneously fine-tune various properties of the drug and would be an invaluable tool during the drug development process.

Effects of 2-amino-8-hydroxyquinoline interaction on the conformation of physiological isomers of human serum albumin.

The methods of synthetic chemistry create small molecules rapidly for screening, and ligand-protein interaction studies provide information on how a potential drug interacts with target or carrier proteins such as serum albumin. In this work, we investigate the interaction of amino derivative of 8-hydroxyquinoline, 2-amino-8-hydroxyquinoline (A8HQ), and the effects of its binding on the conformation of different isomers of human serum albumin (HSA) using multispectroscopic techniques and molecular modeling. We found that B isomer, which exists at pH 9, bound A8HQ (K a = 1.92 ± 0.07 × 10(5) M(-1) at 298 K) more strongly as compared with N isomer (K a = 1.19 ± 0.04 × 10(5) M(-1) at 298 K) of HSA, which is known to exist around pH 6. The binding constant at physiological pH (7.4) was also determined, and the value (K a = 1.38 ± 0.05 × 10(5) M(-1) at 298 K) was found to fall between those for N and B isomers, suggesting that both the N and B isomers exist in an equilibrium in plasma. We also determined the thermodynamic parameters such as changes in enthalpy, entropy , and free energy of binding by measuring the binding at four different temperatures. Based on molecular modeling and thermodynamic studies, we propound that the A8HQ-HSA binding involves mainly hydrophobic interactions and hydrogen bonding. Site-specific marker displacement experiments and molecular modeling showed that the molecule preferably binds in subdomain IIA close to Trp214. A8HQ binding to HSA isomers was found to cause both secondary and tertiary structural alterations in the protein.

Size-Induced Chiral Discrimination Switching by (S)-(-)-2(α-Hydroxyethyl)Benzimidazole-Derived Azacrowns.

(S)-(-)-2-(α-Hydroxyethyl)benzimidazole (1)-derived diastereomeric monoaza-[18]crown-6 compounds 5 and 6 were synthesised with an additional chiral centre bearing a phenyl ring. The aim was to achieve enhanced enantioselective discrimination, compared with monoaza-[15]crown-5 (7). Surprisingly, reversal of enantioselective binding for chiral guest enantiomers between the two differently sized [15]crown-5 and [18]crown-6 azacrowns were discovered; all three were prepared from the same parent compound, 1. To complete the observations, another [18]crown-6-sized azacrown (10) without an additional chiral centre was synthesised from 1 and screened for its enantioselective binding abilities towards the chiral guest enantiomers investigated; these results corroborated the observations. Single-crystal XRD analysis and molecular docking studies revealed that changes to the conformational aspects of [18]crown-6 and [15]crown-5 azacrowns were the major contributing factors to this peculiar behaviour.

Effects of hesperidin, a flavanone glycoside interaction on the conformation, stability, and aggregation of lysozyme: multispectroscopic and molecular dynamic simulation studies?

Hesperidin (HESP), a flavanone glycoside, shows high antioxidant properties and possess ability to go through the blood-brain barrier. Therefore, it could be a potential drug molecule against aggregation based diseases such as Alzheimer's, Parkinson's, and systemic amyloidoses. In this work, we investigated the potential of HESP to interact with hen egg-white lysozyme (HEWL) monomer and prevent its aggregation. The HESP-HEWL binding studies were performed using a fluorescence quenching technique, molecular docking and molecular dynamics simulations. We found a strong interaction of HESP with the lysozyme monomer (Ka, ~ 5 × 10(4) M(-1)) mainly through hydrogen bonding, water bridges, and hydrophobic interactions. We showed that HESP molecule spanned the highly aggregation prone region (amino acid residues 48-101) of HEWL and prevented its fibrillar aggregation. Further, we found that HESP binding completely inhibited amorphous aggregation of the protein induced by disulfide-reducing agent tries-(2-carboxyethyl) phosphine. Conformational and stability studies as followed by various tertiary and secondary structure probes revealed that HESP binding only marginally affected the lysozyme monomer conformation and increased both stability and reversibility of the protein against thermal denaturation. Future studies should investigate detail effects of HESP on solvent dynamics, structure, and toxicity of various aggregates. The answers to these questions will not only target the basic sciences, but also have application in biomedical and biotechnological sciences.

How good are ensembles in improving QSAR models? The case with eCoRIA.

A conceptually new idea in quantitative structure-activity relationships (QSAR) which makes use of ensembles from molecular dynamics (MD) trajectories and information retrieved from enzyme-inhibitor binding thermodynamics is presented in this study. This new methodology, termed ensemble comparative residue interaction analysis (eCoRIA), attempts to overcome the current one chemical-one structure-one parameter value dogma in computational chemistry by modeling the biological activity as a function of molecular descriptors derived from an ensemble of conformers of enzyme-inhibitor complexes. The approach is distinctly different from the standard QSAR methodology which uses a single low-energy conformation or the properties averaged over a set of conformers to correlate with the activity. Each conformational ensemble derived from MD simulations is analyzed for the distribution of the non-bonded interaction energies (steric, electrostatic, and hydrophobic) along with solvation, strain, and entropic energy of the inhibitors with the individual amino acid residues in the receptor and these are correlated to the activity through a QSAR model. The scope of the new method is demonstrated with three diverse enzyme-inhibitor data-sets - glycogen phosphorylase b, human immunodeficiency virus-1 protease and cyclin-dependent kinase 2. The QSAR equations derived from the methodology have revealed all the structure activity relationships previously reported for these classes of molecules as well as uncovered some features that were hitherto unknown and may have a hidden role in driving the ligand-receptor-binding process. Impressive improvements in the predictions of affinity have been achieved compared to other QSAR formalisms namely CoMFA, CoMSIA (receptor-independent QSAR techniques), and CoRIA (a receptor-dependent QSAR technique). eCoRIA could provide an understanding of the thermodynamic properties influencing the ligand-receptor binding over a time scale as sampled by the MD simulation. The advantage of analyzing enzyme-inhibitor interaction energies in a statistical domain is that the noise due to inaccuracies in the potential energy functions can be reduced and mechanistically important interaction terms related to protein-ligand binding specificity can be identified which can assist the medicinal chemists in designing new molecules and biologists in studying the influence of position-specific mutations in the receptor on ligand binding.

Quantifying ligand-receptor interactions for gorge-spanning acetylcholinesterase inhibitors for the treatment of Alzheimer's disease.

There is a need for continued development of acetylcholinesterase (AChE) inhibitors that could prolong the life of acetylcholine in the synaptic cleft and also prevent the aggregation of amyloid peptides associated with Alzheimer's disease. The lack of a 3D-QSAR model which specifically deconvulates the type of interactions and quantifies them in terms of energies has motivated us to report a CoRIA model vis-à-vis the standard 3D-QSAR methods, CoMFA and CoMSIA. The CoRIA model was found to be statistically superior to the CoMFA and CoMSIA models and it could efficiently extract key residues involved in ligand recognition and binding to AChE. These interactions were quantified to gauge the magnitude of their contribution to the biological activity. In order to validate the CoRIA model, a pharmacophore map was first constructed and then used to virtually screen public databases, from which novel scaffolds were cherry picked that were not present in the training set. The biological activities of these novel molecules were then predicted by the CoRIA, CoMFA, and CoMSIA models. The hits identified were purchased and their biological activities were measured by the Ellman's method for AChE inhibition. The predicted activities are in unison with the experimentally measured biological activities.

Targeting dormant tuberculosis bacilli: results for molecules with a novel pyrimidone scaffold.

Our inability to completely control TB has been due in part to the presence of dormant mycobacteria. This also renders drug regimens ineffective and is the prime cause of the appearance of drug-resistant strains. In continuation of our efforts to develop novel antitubercular agents that especially target dormant mycobacteria, a set of 55 new compounds belonging to the pyrimidone class were designed on the basis of CoMFA and CoMSIA studies, and these were synthesized and subsequently tested against both the dormant and virulent BCG strain of M. tuberculosis. Some novel compounds have been identified which selectively inhibit the dormant tuberculosis bacilli with significantly low IC50 values. This study reports the second molecule after TMC-207, having the ability to inhibit tuberculosis bacilli exclusively in its dormant phase. The synthesis was accomplished by a modified multicomponent Biginelli reaction. A classification model was generated using the binary QSAR approach--recursive partitioning (RP) to identify structural characteristics related to the activity. Physicochemical, structural, topological, connectivity indices, and E-state key descriptors were used for generation of the decision tree. The decision tree could provide insights into structure-activity relationships that will guide the design of more potent inhibitors.