Current Drug Discovery Technologies (v.14, #1)

Meet Our Editorial Board Member by Michael S. Wolfe (1-1).

An Evidence-Based Review on Medicinal Value of Clays in Traditional Persian Medicine by Ayda Hosseinkhani, Hashem Montaseri, Ammar Hosamo, Mohammad Mehdi Zarshenas (2-7).
The use of earths and clays for medical purposes dates back to antiquity. In recent years, there has been an increasing interest in researches on traditional remedies in the hope of discovering new drug. Iran is an ancient country with a medical backbone acquired from the experiences of ancient Persian scholars, who had made a great contribution to the development of the medical sciences. Many medical and pharmaceutical books by early Persian scientists still exist and may have the potential of leading researchers to new drug discoveries. Owing to the emergence of new and antimicrobial-resistant infections, present-day medicine has recently begun focusing on medicinal earths and clays especially as mineral antimicrobials. The current study is, therefore, aimed at gathering information regarding medicinal clays in traditional Persian medicine (TPM). Five main Persian materia medica with the key word 'tin' (clay) and current databases such as PubMed, Scopus, ScienceDirect, and Google Scholar were searched by key words 'white, green, red, maroon, violet, black, grey and pink clays' and 'pharmacological effects'. Twenty three clays were found in Persian manuscripts. Although their mineralogical compositions are unknown, different pharmacological properties have been attributed to these mineral medicaments. Clay's properties were widely used in medieval times for the treatment of infections to poisoning. They were also used in compound formulations, possibly for their pharmaceutical formulation modifying effects. Modern scientific proofs have also been found in many of the medicinal clays reported in Persian manuscripts. Although many of the reported clays are still unknown, their characterization may lead to new medicinal developments. Novel analytical methods available today make it possible to elucidate the chemical compositions of these minerals as parameters responsible for their medicinal effects.

In Silico Design of New Inhibitors of Guanine Phosphoribosyltransferase (GPRT) from Giardia lamblia as Antiparasitic Drug Candidates by Gustavo M. das Neves, Luciano P. Kagami, Ricardo P. Rodrigues, Vinícius B. da Silva, Vera L. Eifler-Lima, Daniel F. Kawano (8-24).
Background: Guanine phosphoribosyltransferase (GPRT) is a very attractive target for the development of new drugs against G. lamblia because of its critical role in the synthesis of DNA and RNA. Herein we report the use of in silico approaches to identify potential G. lamblia GPRT inhibitors.

Methods: Analyses of the binding site of the enzyme accomplished through the use of several methods allowed the construction of a pharmacophore model, which was screened against a database of commercial substances. The resulting retrieved compounds were then screened against GPRT by consensus docking with two different methods, and the top 10% scored compounds had their poses visually inspected. Root Mean Square Deviation (RMSD) values ? 2.0 A were used to define a consensual pose while RMSD values between 2 and 3 A defined a partial consensus. Main toxicity endpoints were predicted through substructural analyses.

Results: From the 1,230 compounds retrieved in the pharmacophore-based screening, eleven had their binding modes consensually ascribed by the docking methods, suggesting a better selectivity for the parasite enzyme in comparison to the human counterpart by avoiding steric bumps with a flexible loop in the human enzyme binding site. One compound, ZINC38139588, was predicted to be totally devoid of toxicity, being perhaps the most promising of this series.

Conclusion: Through rigorously validated docking protocols, we predicted the binding mode of these compounds in the GPRT binding site. The use of a consensus docking strategy yielded more reliable predictions of the binding modes to guide the future biological assays.

QSAR Studies, Synthesis and Antibacterial Assessment of New Inhibitors Against Multidrug-Resistant Mycobacterium tuberculosis by Vasyl Kovalishyn, Volodymyr Brovarets, Volodymyr Blagodatnyi, Iryna Kopernyk, Diana Hodyna, Svitlana Chumachenko, Oleg Shablykin, Oleksandr Kozachenko, Myhailo Vovk, Marianna Barus, Myhailo Bratenko, Larysa Metelytsia (25-38).
Background: The increasing rate of appearance of multidrug-resistant strains of Mycobacterium tuberculosis (MDR-TB) is a serious problem at the present time. MDR-TB forms do not respond to the standard treatment with the commonly used drugs and can take some years or more to treat with drugs that are less potent, more toxic and much more expensive.

Objective: The goal of this work is to identify the novel effective drug candidates active against MDR-TB strains through the use of methods of cheminformatics and computeraided drug design.

Methods: This paper describes Quantitative Structure-Activity Relationships (QSAR) studies using Artificial Neural Networks, synthesis and in vitro antitubercular activity of several potent compounds against H37Rv and resistant Mycobacterium tuberculosis (Mtb) strains.

Results: Eight QSAR models were built using various types of descriptors with four publicly available structurally diverse datasets, including recent data from PubChem and ChEMBL. The predictive power of the obtained QSAR models was evaluated with a cross-validation procedure, giving a q2=0.74-0.78 for regression models and overall accuracy 78.9-94.4% for classification models. The external test sets were predicted with accuracies in the range of 84.1-95.0% (for the active/inactive classifications) and q2=0.80- 0.83 for regressions. The 15 synthesized compounds showed inhibitory activity against H37Rv strain whereas the compounds 1-7 were also active against resistant Mtb strain (resistant to isoniazid and rifampicin).

Conclusion: The results indicated that compounds 1-7 could serve as promising leads for further optimization as novel antibacterial inhibitors, in particular, for the treatment of drug resistance of Mtb forms.

Designing Potential Antitrypanosomal Thiazol-2-ethylamines through Predictive Regression Based and Classification Based QSAR Analyses by Sk. Abdul Amin, Nilanjan Adhikari, Sonam Bhargava, Tarun Jha, Shovanlal Gayen (39-52).
Background: Thiazol-2-ethylamine is recently reported to be an interesting scaffold having antitrypansomal activity for the treatment of sleeping sickness.

Methods: Statistically significant, robust and validated regression-based QSAR models are constructed for a series of antitrypansomal thiazol-2-ethylamines. Moreover, classification-based QSAR analyses (linear discriminant analysis and Bayesian classification modelling) are also performed to identify the important structural features controlling antitrypanosomal activity.

Results: Molecular fingerprints such as N-piperidinyl and 2-fluorophenyl functions may be responsible for higher antitrypanosomal activity whereas compounds with chlorophenyl moiety and compounds with unsaturated nitrogen atom possess poor activity. These results are supported by the regression-based QSAR model as well as the SAR observations.

Conclusion: Finally, fifteen new compounds bearing thiazol-2-ethylamine scaffold are designed and predicted along with their drug-likeness properties. Therefore, this study may provide important structural aspects of designing new antitrypansomal agents with higher activity.

The Biology of β-D-mannuronic acid (M2000) on Human Dendritic Cell Based on MicroRNA-155 and MicroRNA-221 by Nakisa Tabrizian, Nazanin Arjomand Fard, Ali Farazmand, Rahil Eftekhari, Farzaneh Tofighi Zavareh, Abbas Mirshafiey (53-58).
Background: The aim of this study was to evaluate the effect of Β-Dmannuronic acid (M2000) on related miRNAs to dendritic cells (DCs) differentiation. DC-based immunosuppressive drugs can suppress the progression of autoimmune diseases, however, their notable side effects in increasing the risk of infectious diseases and cancers should be considered. The β-D-mannuronic acid, as a novel non-steroidal anti-inflammatory agent, has been tested in various experimental models.

Method: The effect of M2000 on expression of miRNA-155 and miRNA-221 was examined. To investigate how M2000 affects differentiation of human dendritic DCs in a defined inflammatory environment, human peripheral blood mononuclear cells were isolated from healthy blood and the monocytes were purified using anti-CD14 microbeads. The so isolated monocytes were subsequently incubated in the presence of M2000 in two different doses (3 and 6 mMol/well) adding granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 for inducing monocytes to immature DC and lipopolysaccharide for running DC differentiation. The expression of miRNA-155 and miRNA-221 were examined with Real Time PCR.

Results: The results demonstrate that M2000 has no significant side effect on expression of miR-155 and miR-221 in both immature DC and mature DC process in vitro.

Conclusion: Our findings show that β-D-mannuronic acid is a safe agent which has no adverse effect on regulatory miRNA-155 and miRNA-221 in dendritic cells.

Background: Protein three-dimensional structures are very much important in terms of functional and evolutionary context. In the present work we evaluated the snake venom constituent cytotoxin, short neurotoxin and related non-toxin proteins of other chordates with reference to structure prediction, validation of the models, distribution of secondary structural elements, hydrophobicity molecular surface analysis, functional annotation and functionally critical binding site identification with the assistance of different bioinformatical tools.

Methods: Homology models have been generated with the help of Swiss-model and ITASSER suite during the present study. Afterwards the refined structural models were validated with standard methods. For functional annotation of protein molecules we used Protein Information Resource (PIR) database. The functionally critical amino acids and ligand- binding site (LBS) of the proteins (modeled) was determined using the COACH program.

Results: Structural analysis of snake venom toxin proteins and related non-toxin proteins of other chordates elucidated their structural level conservation of molecular structural surfaces and biophysical characteristics to different extents. Different structural level improvement strategies were observed which are necessary for better system dependent adaptation to diverse biological environment and functional necessities of these protein molecules.

Conclusion: Molecular models and their structural characterization of these proteins as documented in this study may provide a valuable aid for drug designing in future.