CoRILISA: A Local Similarity Based Receptor Dependent QSAR Method

Molecular similarity methods have played a crucial role in the success of structure-based and computer-assisted drug design. However, with the exception of CoMSIA, the current approaches for estimating molecular similarity yield a global picture thereby providing limited information about the local spatial molecular features responsible for the variation of activity with the 3D structure. Application of molecular similarity measures, each related to the <i>functional “pieces”</i> of a ligand–receptor complex, is advantageous over a composite molecular similarity alone and will provide more insights to rationally interpret the activity based on the receptor and ligand structural features. Building on the ideas of our previously published methodologiesCoRIA and LISA, we present here a local molecular similarity based receptor dependent QSAR method termed CoRILISA which is a hybrid of the two approaches. The method improves on previous techniques by inclusion of receptor attributes for the calculation and comparison of similarity between molecules. For validation studies, the CoRILISA methodology was applied on three large and diverse data setsglycogen phosphorylase <i>b</i> (GP<i>b</i>), human immunodeficiency virus-1 protease (HIV PR), and cyclin dependent kinase 2 (CDK2) inhibitors. The statistics of the CoRILISA models were benchmarked against the standard CoRIA approach and with other published approaches. The CoRILISA models were found to be significantly better, especially in terms of the predictivity for the test set. CoRILISA is able to identify the thermodynamic properties associated with residues that define the active site and modulate the variation in the activity of the molecules. It is a useful tool in the fragment-based drug discovery approach for ligand activity prediction

4-Thiazolidinone Based 5-Arylidene Hybrids: Design, Synthesis, Antimicrobial Activity, and Molecular Docking Studies

In recent years, the most pressing challenge in drug development has been the fight against bacterial drug resistance. Microbes have developed resistance against the present classes of antibiotics, necessitating the development of new antibiotics capable of replacing less effective drugs commercially accessible in the market. In order to achieve this, a straightforward technique for the synthesis of 4-thiazolidinone-based pyrazole-pyridine hybrids was designed (5a–o). The hybrids were characterized using spectroscopic techniques and tested for antimicrobial efficacy against a variety of bacterial and fungal species. The MIC value of compounds 5d, 5f, 5j, 5 l, 5 m, and 5o against tested bacterial strains was 62.5 μg/mL. Compound 5i showed a MIC value of 250 μg/mL against Candida albicans, which is twice the activity of the standard drug. Furthermore, to rationalize the antimicrobial finding and to gain an insight into the plausible mechanism of action, molecular docking study was performed against microbial DNA gyrase. A very significant correlation obtained between the in silico binding affinity and the antimicrobial activity could set an excellent platform for structure based drug design.</p

1,2,3-Triazolyl Phenylhydrazones as Antioxidant Agents: An Ultrasound Promoted Catalyst-Free Synthesis and Molecular Docking Study

An efficient, ultrasound assisted catalyst-free, green protocol has been developed for the synthesis of 1,2,3-triazolyl phenylhydrazone derivatives under environmentally benign condition. The antioxidant activity for all the synthesized derivatives were evaluated in vitro by using 1,1-diphenylpicrylhydrazyl (DPPH) radical scavenging method. The compounds 6a, 6e, 6f, and 6i were shows an excellent antioxidant activity than the standard drug butylated hydroxy toluene with IC50 values in the range 12.03 ± 0.11–14.07 ± 0.31 µg/mL. Molecular docking study was also performed to elaborate their possible interactions with Myeloperoxidase enzyme. Furthermore, in silico ADME properties for all the compounds were also studied. </p

New pimarane diterpenes and other antimycobacterial metabolites from <i>Anisochilus verticillatus</i>

<div><p>Phytochemical investigation of the acetone extract of the aerial parts of <i>Anisochilus verticillatus</i> afforded a new 8,9-secopimarane diterpene (<b>1</b>), two new isopimarane diterpenes (<b>2</b>, <b>3</b>) and the known ursolic acid (<b>4</b>), α-amyrin (<b>5</b>), β-amyrin (<b>6</b>), stigmast-5-en-3-one (<b>7</b>) and hydroxychavicol (<b>8</b>). Structures of the new compounds were elucidated with the help of 1D and 2D nuclear magnetic resonance spectroscopic data, and single crystal X-ray crystallography of compound <b>3</b>. Compounds <b>2</b> and <b>8</b> inhibited <i>Mycobacterium tuberculosis</i> H37Ra with an IC₅₀ of 11.3 (IC₉₀ of 20.0 μg/mL) and 12.5 μg/mL, respectively. Correspondingly, molecular docking studies with Extra Precision Glide revealed a correlation between score and biological activity for these compounds to describe the molecular basis for the most significant SAR results.</p></div

Synthesis and Antitubercular Activity of New Benzo[<i>b</i>]thiophenes

<i>In vitro</i> and <i>ex vivo</i> efficacies of four series of benzo­[<i>b</i>]­thiophene-2-carboxylic acid derivatives were studied against <i>Mycobacterium tuberculosis</i> H37Ra (MTB). Benzo­[<i>b</i>]­thiophenes were also tested <i>in vitro</i> against multidrug resistant <i>Mycobacterium tuberculosis</i> H37Ra (MDR-MTB), and <b>7b</b> was found to be highly active against A- and D-MDR-MTB/MTB (MIC ranges 2.73–22.86 μg/mL). The activity of all benzo­[<i>b</i>]­thiophenes against <i>M. bovis</i> BCG (BCG) was also assessed grown under aerobic and under conditions of oxygen depletion. Compounds <b>8c</b> and <b>8g</b> showed significant activity with MICs of 0.60 and 0.61 μg/mL against dormant BCG. The low cytotoxicity and high selectivity index data against human cancer cell lines, HeLa, Panc-1, and THP-1 indicate the potential importance of the development of benzo­[<i>b</i>]­thiophene-based 1,3-diketones and flavones as lead candidates to treat mycobacterial infections. Molecular docking studies into the active site of DprE1 (Decaprenylphosphoryl-β-d-ribose-2′-epimerase) enzyme revealed a similar binding mode to native ligand in the crystal structure thereby helping to understand the ligand–protein interactions and establish a structural basis for inhibition of <i>MTB</i>. In summary, its good activity in <i>in vitro</i> and <i>ex vivo</i> model, as well as its activity against multidrug-resistant <i>M</i>. <i>tuberculosis</i> H37Ra in a potentially latent state, makes <b>7b</b> an attractive drug candidate for the therapy of tuberculosis

Synthesis, biological evaluation, and molecular docking study of pyridine clubbed 1,3,4-oxadiazoles as potential antituberculars

<p>A series of pyridine clubbed 1,3,4-oxadiazole derivatives were efficiently synthesized, characterized by standard spectral techniques and evaluated for their <i>in vitro</i> antitubercular activity against <i>Mycobacterium tuberculosis</i> (MTB) H₃₇Ra and <i>Mycobacterium bovis</i> BCG in active and dormant state using an established methods. Compounds <b>5a, 5m</b>, and <b>5t</b> were identified as the most active compounds against MTB. Molecular docking was performed against MTB enoyl-ACP (CoA) reductase (FabI/ENR/InhA) enzyme to predict the binding modes and affinity. The theoretical predictions from molecular docking could establish a link between the observed biological activity and the binding affinity shedding light into specific bonded and non-bonded interactions influencing the activity. The active compounds were studied for cytotoxicity against three cell lines and were found to be non-cytotoxic. Specificity of these compounds was checked by screening them for their antibacterial activity against four bacterial strains.</p

<i>In vitro</i> and <i>ex vivo</i> antitubercular activity of diarylheptanoids from the rhizomes of <i>Alpinia officinarum</i> Hance

<p>Phytochemical investigation of methanol extract of the rhizomes of <i>Alpinia officinarum</i> Hance afforded four known diarylheptanoids 1,7-diphenylhept-4-en-3-one (<b>1</b>), 5-hydroxy-1,7-diphenyl-3-heptanone (<b>2</b>), 5-hydroxy-7-(4″-hydroxy-3″-methoxyphenyl)-1-phenyl-3-heptanone (<b>3</b>), and 7-(4″-hydroxy-3″-methoxyphenyl)-1-phenyl heptan-3-one (<b>4</b>).The acetate derivative of (<b>4</b>), 7-(4″-actetate-3″-methoxy phenyl)-1-phenyl heptan-3-one (<b>5</b>), was prepared. These diarylheptanoids exhibited promising <i>in vitro</i> and <i>ex vivo</i> antitubercular activity for the first time against dormant <i>Mycobacterium tuberculosis</i> H37Ra with the IC₅₀ values between 0.34<b>–</b>47.69 and 0.13–22.91 μM, respectively. All compounds showed comparable activity against <i>Mycobacterium bovis</i> BCG (dormant phage) and did not show any activity against two gram + ve and two gram –ve bacterial strains. These compounds were also weakly cytotoxic up to 300 μM against three human cancer cell lines THP-1, Panc-1 and A549.</p