A novel set of ss-N-biaryl ether sulfonamide hydroxamates as potential MMPs inhibitors: Molecular dynamics simulations and molecular properties evaluation

Matrix metalloproteinases (MMPs) constitute a family of zinc-dependent proteases involved in the extracellular matrix degradation. MMP-2 and MMP9 are overexpressed in several human cancer types, including melanoma, thus the development of new compounds to inhibit MMPs' activity is desirable. Molecular dynamic simulation and molecular properties calculations were performed on a set of novel beta-N-biaryl ether sulfonamide-based hydroxamates, reported as MMP-2 and MMP-9 inhibitors, for providing data to develop an exploratory analysis. Thermodynamic, electronic, and steric descriptors have significantly discriminated highly active from moderately and less active inhibitors of MMP-2 whereas apparent partition coefficient at pH 1.5 was also significant for the MMP-9 data set. Compound 47 was considered an outlier in all analysis, indicating the presence of a bulky substituent group in R3 is crucial to this set of inhibitors for the establishment of molecular interactions with the S1 subsite of both enzymes, but there is a limit. (C) 2012 Wiley Periodicals, Inc.

Pyridine Alkaloids from Senna multijuga As Acetylcholinesterase Inhibitors

As part of an ongoing research project on Senna and Cassia species, five new pyridine alkaloids, namely, 12'-hydroxy-7'-multijuguinol (1), 12'-hydroxy-8'-multijuguinol (2), methyl multijuguinate (3), 7'-multijuguinol (4), and 8'-multijuguinol (5), were isolated from the leaves of Senna multijuga (syn. Cassia multijuga). Their structures were elucidated on the basis of spectroscopic data analysis. Mass spectrometry was used for confirmation of the positions of the hydroxy groups in the side-chains of 1, 2, 4, and 5. All compounds exhibited weak in vitro acetylcholinesterase inhibitory activity as compared with the standard compound physostigmine.

Synthesis, Biological Evaluation, And Molecular Modeling of Chalcone Derivatives As Potent Inhibitors of Mycobacterium tuberculosis Protein Tyrosine Phosphatases (PtpA and PtpB)

Tuberculosis (TB) is a major infectious disease caused by Mycobacterium tuberculosis (Mtb). According to the World Health Organization (WHO), about 1.8 million people die from TB and 10 million new cases are recorded each year. Recently, a new series of naphthylchalcones has been identified as inhibitors of Mtb protein tyrosine phosphatases (PTPs). In this work, 100 chalcones were designed, synthesized, and investigated for their inhibitory properties against MtbPtps. Structure-activity relationships (SAR) were developed, leading to the discovery of new potent inhibitors with IC50 values in the low-micromolar range. Kinetic studies revealed competitive inhibition and high selectivity toward the Mtb enzymes. Molecular modeling investigations were carried out with the aim of revealing the most relevant structural requirements underlying the binding affinity and selectivity of this series of inhibitors as potential anti-TB drugs.

Effect of dental tissue conditioners and matrix metalloproteinase inhibitors on type I collagen microstructure analyzed by Fourier transform infrared spectroscopy

This study aimed to evaluate the chemical interaction of collagen with some substances usually applied in dental treatments to increase the durability of adhesive restorations to dentin. Initially, the similarity between human dentin collagen and type I collagen obtained from commercial bovine membranes of Achilles deep tendon was compared by the Attenuated Total Reflectance technique of Fourier Transform Infrared (ATR-FTIR) spectroscopy. Finally, the effects of application of 35% phosphoric acid, 0.1M ethylenediaminetetraacetic acid (EDTA), 2% chlorhexidine, and 6.5% proanthocyanidin solution on microstructure of collagen and in the integrity of its triple helix were also evaluated by ATR-FTIR. It was observed that the commercial type I collagen can be used as an efficient substitute for demineralized human dentin in studies that use spectroscopy analysis. The 35% phosphoric acid significantly altered the organic content of amides, proline and hydroxyproline of type I collagen. The surface treatment with 0.1M EDTA, 2% chlorhexidine, or 6.5% proanthocyanidin did not promote deleterious structural changes to the collagen triple helix. The application of 6.5% proanthocyanidin on collagen promoted hydrogen bond formation. (c) 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2012.

Structure-based drug design studies on a series of aldolase inhibitors

Human African trypanosomiasis, also known as sleeping sickness, is a major cause of death in Africa, and for which there are no safe and effective treatments available. The enzyme aldolase from Trypanosoma brucei is an attractive, validated target for drug development. A series of alkyl‑glycolamido and alkyl-monoglycolate derivatives was studied employing a combination of drug design approaches. Three-dimensional quantitative structure-activity relationships (3D QSAR) models were generated using the comparative molecular field analysis (CoMFA). Significant results were obtained for the best QSAR model (r2 = 0.95, non-cross-validated correlation coefficient, and q2 = 0.80, cross-validated correlation coefficient), indicating its predictive ability for untested compounds. The model was then used to predict values of the dependent variables (pKi) of an external test set,the predicted values were in good agreement with the experimental results. The integration of 3D QSAR, molecular docking and molecular dynamics simulations provided further insight into the structural basis for selective inhibition of the target enzyme.