A Comparative Study of 1D Descriptors Supported CoMFA and CoMSIA QSAR Models to Gain Novel Insights into 1,2,4-Triazoles Acting As Antitubercular Agents

2020 ◽  
Vol 16 ◽  
Author(s):  
Rajdeep Ray ◽  
Gautham Shenoy ◽  
N V Ganesh Kumar Tummalapalli
Keyword(s):  
External Validation ◽  
Antitubercular Activity ◽  
New Drugs ◽  
Rational Approach ◽  
Antitubercular Drugs ◽  
Comfa Model ◽  
Qsar Models ◽  
Structural Insights ◽  
The Way

: Tuberculosis is one of the leading cause for deaths due to infectious disease worldwide. There is an urgent need for developing new drugs due to the rising incidents of drug resistance. Triazoles have previously been reported to show antitubercular activity. Various computational tools pave the way for a rational approach in understanding the structural importance of these compounds in inhibiting Mycobacterium tuberculosis growth. The aim of this study is to develop and compare two different QSAR models based on a set of previously reported molecules and use the best one for gaining structural insights in to the Triazole molecules. In the current study, two separate models were generated with CoMFA and CoMSIA descriptors respectively based on a dataset of triazole molecules showing antitubercular activity. Several one dimensional (1D) descriptors were added to each of the models and the validation results and the contour data generated from them were compared. The best model was studied to give a detailed understanding of the triazole molecules and their role in the antitubercular activity.The r2, q2, predicted r2 and SEP (Standard error of prediction) for the CoMFA model were 0.866, 0.573, 0.119 and 0.736 respectively and for the CoMSIA model the r2, q2, predicted r2 and SEP were calculated to be 0.998, 0.634, 0.013 and 0.869 respectively. Although both the QSAR models produced acceptable internal and external validation scores but the CoMSIA results were significantly better. The CoMSIA contours also provided a better match than CoMFA with most of the features of the active compound 30b. Hence, the CoMSIA model was chosen and its contours were explored for gaining structural insights on the triazole molecules. The CoMSIA contours helped us to understand the role of several atoms and groups of the triazole molecules in their biological activity. The possibilities for substitution in the triazole compounds that would enhance the activity were also analysed. Thus, this study paves the way for designing new antitubercular drugs in future.

ATP Synthase Inhibitors as Anti-tubercular Agents: QSAR Studies in Novel Substituted Quinolines

2020 ◽  
Vol 20 (29) ◽  
pp. 2723-2734
Author(s):  
Anil K. Saxena ◽  
Muneer Alam
Keyword(s):  
Atp Synthase ◽  
Antitubercular Activity ◽  
Pharmacophore Modeling ◽  
World Health ◽  
Data Set ◽  
Antitubercular Drugs ◽  
Qsar Analysis ◽  
Qsar Studies ◽  
Substituted Quinolines ◽  
Qsar Models

Background: Tuberculosis (TB) is a major infectious disease caused by Mycobacterium Tuberculosis. As per the World Health Organization (WHO) report of 2019, there were 1.5 million deaths in the year 2018, mainly because of multi- and extensively drug-resistant tuberculosis (MDR & XDR-TB). Among several antitubercular drugs in clinical trials, bedaquiline (TMC207) is a highly promising drug that was approved by the FDA in 2012 and marketed in 2016 for the treatment of multidrug resistant TB in combination with other drugs. Bedaquiline acts on mycobacterial ATP synthase and is highly effective in replicating as well as on dormant mycobacteria. Several series of substituted quinolines have been reported with their antitubercular and ATP synthase inhibitory activity. Methods: To understand the role of physicochemical parameters like hydrophobicity, electronic and steric factors in eliciting the biological response, the Quantitative structure-activity relationship (QSAR) studies have been carried out using the computed parameters as independent variable and activity (-log IC50/MIC) as the dependent variable. Results: The developed QSAR models in terms of positively contributing Molar Refractivity (MR) and negatively contributing Partition Coefficient (PC) and Connolly Molecular Area (CMA) parameters have high predictivity as also shown on external data set and the mean value of the computed 3D parameters of enantiomers may be used in QSAR analysis for racemic compounds. Conclusion: These results are also substantiated by pharmacophore modeling. The similar dependence of antitubercular activity against whole-cell M.Tb.H37Rv on MR and CMA suggests ATP synthase as the main target for antitubercular activity and the QSAR models may be useful in the identification of novel antitubercular agents.

Nomogram-based risk prediction of local and distant relapse after radical cystectomy, and role of perioperative chemotherapy, in patients with muscle-invasive bladder cancer (MIBC): A multicenter study.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 448-448
Author(s):  
Andrea Necchi ◽  
Gregory Russell Pond ◽  
Elizabeth R. Plimack ◽  
Guenter Niegisch ◽  
Evan Y. Yu ◽  
...  
Keyword(s):  
Radical Cystectomy ◽  
Risk Prediction ◽  
Cox Regression ◽  
Statistical Significance ◽  
External Validation ◽  
New Drugs ◽  
Perioperative Chemotherapy ◽  
Distant Relapse ◽  
Pn Stage

448 Background: Neoadjuvant and adjuvant chemotherapy improve relapse-free survival (RFS) and overall survival of patients (pts) with MIBC. Limited information is available regarding risk prediction of local (RL) vs. distant relapse (RD), including role of perioperative chemotherapy (POC), added to radical cystectomy (Cy). Methods: Data from 1,559 pts, treated at 29 centers from the U.S., Europe, Israel, and Canada, were collected. Pts received Cy for MIBC from 02/90 to 12/13. Of these pts, 782 (50.2%) received POC and Cy, 777 (49.8%) Cy alone. RL and RD were defined as follows: pelvic lymph-nodes/soft tissue only and any extra-pelvic recurrences, respectively. Cumulative incidence methods were used to estimate time-to-(TT) RL/RD, which accounts for the competing risk of other types of relapse. Univariable and multivariable (MVA) Cox regression analyses were performed from the complete-case dataset (n = 1,082). Risk groups were defined according to the number of adverse factors, with corresponding nomogram-based RL and RD risk estimation. All tests were two-sided and statistical significance was defined as a p-value of 0.05 or less. Results: A total of 830 pts (55%) developed a relapse, 447 in the Cy group and 383 in the Cy+POC group. On MVA, POC administration was associated with longer TTRL (p < 0.001) and TTRD (p < 0.001). Other factors associated with RL: histology (non-UC, odds ratio [OR] = 1.47, 95%CI: 1.07-2.01, p = 0.022), pT-stage (p < 0.001), pN-stage (p = 0.038), surgical margins (p < 0.001). For RD: Charlson score (p = 0.006), pT-stage (p < 0.001), pN-stage (p < 0.001). The c-index of the model for RL was 0.685 (95% bootstrapped CI: 0.664-0.718), and for RD was 0.684 (0.655-0.721). Three risk group categories were obtained for both endpoints (0, 1-2, and > 2 risk factors). Results were confirmed after applying 90-day or 180-day landmark analyses, pending external validation. Conclusions: In the largest study that separately analyzed RL and RD risk, we were able to provide risk tools that may be used to optimize locoregional treatments and compare POC benchmark with new drugs in the perioperative setting.

scholarly journals Cinnamic Derivatives as Antitubercular Agents: Characterization by Quantitative Structure–Activity Relationship Studies

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 456
Author(s):  
Cátia Teixeira ◽  
Cristina Ventura ◽  
José R. B. Gomes ◽  
Paula Gomes ◽  
Filomena Martins
Keyword(s):  
Linear Regression Analysis ◽  
External Validation ◽  
Infectious Agent ◽  
Antitubercular Activity ◽  
Multiple Linear Regression Analysis ◽  
Quantitative Structure Activity Relationship ◽  
Quantitative Structure ◽  
Antitubercular Drugs ◽  
Resistant Tuberculosis ◽  
Structure Activity

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains one of the top ten causes of death worldwide and the main cause of mortality from a single infectious agent. The upsurge of multi- and extensively-drug resistant tuberculosis cases calls for an urgent need to develop new and more effective antitubercular drugs. As the cinnamoyl scaffold is a privileged and important pharmacophore in medicinal chemistry, some studies were conducted to find novel cinnamic acid derivatives (CAD) potentially active against tuberculosis. In this context, we have engaged in the setting up of a quantitative structure–activity relationships (QSAR) strategy to: (i) derive through multiple linear regression analysis a statistically significant model to describe the antitubercular activity of CAD towards wild-type Mtb; and (ii) identify the most relevant properties with an impact on the antitubercular behavior of those derivatives. The best-found model involved only geometrical and electronic CAD related properties and was successfully challenged through strict internal and external validation procedures. The physicochemical information encoded by the identified descriptors can be used to propose specific structural modifications to design better CAD antitubercular compounds.

The Role of VLBI in the Establishment of Coordinate Systems

1975 ◽  
Vol 26 ◽  
pp. 293-295 ◽  
Author(s):  
I. Zhongolovitch
Keyword(s):  
General Solution ◽  
Future Development ◽  
Rational Approach ◽  
Radio Telescopes ◽  
Coordinate Systems ◽  
Tectonic Plates ◽  
Astronomical Observations ◽  
Optical Instruments ◽  
Fundamental Polyhedron

Considering the future development and general solution of the problem under consideration and also the high precision attainable by astronomical observations, the following procedure may be the most rational approach:1. On the main tectonic plates of the Earth’s crust, powerful movable radio telescopes should be mounted at the same points where standard optical instruments are installed. There should be two stations separated by a distance of about 6 to 8000 kilometers on each plate. Thus, we obtain a fundamental polyhedron embracing the whole Earth with about 10 to 12 apexes, and with its sides represented by VLBI.

MANUSCRIPT EVIDENCE FOR ALPHABET-SWITCHING IN THE WORKS OF CICERO: COMMON NOUNS AND ADJECTIVES

2018 ◽  
Vol 68 (2) ◽  
pp. 498-516
Author(s):  
Neil O'Sullivan
Keyword(s):  
Recent Work ◽  
Code Switching ◽  
Consistent Pattern ◽  
Current Interest ◽  
Reliable Transmission ◽  
Accurate Record ◽  
The Way

Of the hundreds of Greek common nouns and adjectives preserved in our MSS of Cicero, about three dozen are found written in the Latin alphabet as well as in the Greek. So we find, alongside συμπάθεια, also sympathia, and ἱστορικός as well as historicus. This sort of variation has been termed alphabet-switching; it has received little attention in connection with Cicero, even though it is relevant to subjects of current interest such as his bilingualism and the role of code-switching and loanwords in his works. Rather than addressing these issues directly, this discussion sets out information about the way in which the words are written in our surviving MSS of Cicero and takes further some recent work on the presentation of Greek words in Latin texts. It argues that, for the most part, coherent patterns and explanations can be found in the alphabetic choices exhibited by them, or at least by the earliest of them when there is conflict in the paradosis, and that this coherence is evidence for a generally reliable transmission of Cicero's original choices. While a lack of coherence might indicate unreliable transmission, or even an indifference on Cicero's part, a consistent pattern can only really be explained as an accurate record of coherent alphabet choice made by Cicero when writing Greek words.

The adaptation of design thinking in auditing

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Linda MEIJER-WASSENAAR ◽  
Diny VAN EST
Keyword(s):  
The Netherlands ◽  
Design Thinking ◽  
Public Organizations ◽  
Design Framework ◽  
The Right ◽  
The Way

How can a supreme audit institution (SAI) use design thinking in auditing? SAIs audit the way taxpayers’ money is collected and spent. Adding design thinking to their activities is not to be taken lightly. SAIs independently check whether public organizations have done the right things in the right way, but the organizations might not be willing to act upon a SAI’s recommendations. Can you imagine the role of design in audits? In this paper we share our experiences of some design approaches in the work of one SAI: the Netherlands Court of Audit (NCA). Design thinking needs to be adapted (Dorst, 2015a) before it can be used by SAIs such as the NCA in order to reflect their independent, autonomous status. To dive deeper into design thinking, Buchanan’s design framework (2015) and different ways of reasoning (Dorst, 2015b) are used to explore how design thinking can be adapted for audits.

Bad Dreams and Secret Artists: Translating Freud into Literature

2002 ◽  
Vol 4 (2) ◽  
pp. 127-139 ◽  
Author(s):  
Ian Patterson
Keyword(s):  
Sigmund Freud ◽  
Ordinary Language ◽  
Close Reading ◽  
Careful Attention ◽  
Popular Approach ◽  
English Reader ◽  
Creative Writer ◽  
The Many ◽  
The Way

This article addresses the increasingly popular approach to Freud and his work which sees him primarily as a literary writer rather than a psychologist, and takes this as the context for an examination of Joyce Crick's recent translation of The Interpretation of Dreams. It claims that translation lies at the heart of psychoanalysis, and that the many interlocking and overlapping implications of the word need to be granted a greater degree of complexity. Those who argue that Freud is really a creative writer are themselves doing a work of translation, and one which fails to pay sufficiently careful attention to the role of translation in writing itself (including the notion of repression itself as a failure to translate). Lesley Chamberlain's The Secret Artist: A Close Reading of Sigmund Freud is taken as an example of the way Freud gets translated into a novelist or an artist, and her claims for his ‘bizarre poems' are criticized. The rest of the article looks closely at Crick's new translation and its claim to be restoring Freud the stylist, an ordinary language Freud, to the English reader. The experience of reading Crick's translation is compared with that of reading Strachey's, rather to the latter's advantage.

Prawne aspekty eutanazji w Holandii

2016 ◽  
Vol 14 (3) ◽  
pp. 243-253
Author(s):  
Grzegorz Stefanowicz
Keyword(s):  
The Netherlands ◽  
Assisted Suicide ◽  
Public Authority ◽  
Dutch Society ◽  
On Demand ◽  
Limited Length ◽  
The Law ◽  
Death On Demand ◽  
The Way

This article undertakes to show the way that has led to the statutory decriminalization of euthanasia-related murder and assisted suicide in the Kingdom of the Netherlands. It presents the evolution of the views held by Dutch society on the euthanasia related practice, in the consequence of which death on demand has become legal after less than thirty years. Due attention is paid to the role of organs of public authority in these changes, with a particular emphasis put on the role of the Dutch Parliament – the States General. Because of scarcity of space and limited length of the article, the change in the attitudes toward euthanasia, which has taken place in the Netherlands, is presented in a synthetic way – from the first discussions on admissibility of a euthanasia-related murder carried out in the 1970s, through the practice of killing patients at their request, which was against the law at that time, but with years began more and more acceptable, up to the statutory decriminalization of euthanasia by the Dutch Parliament, made with the support of the majority of society.

The Role of Music and Allied Arts in Public Writings on Cultural Diversity: “People of Sri Lanka”

2020 ◽  
Vol 6 ◽  
pp. 93-100
Author(s):  
Gisa Jähnichen
Keyword(s):  
Sri Lanka ◽  
Cultural Diversity ◽  
South Asia ◽  
Case Studies ◽  
Sri Lankan ◽  
Culturally Different ◽  
The World ◽  
Official Languages ◽  
The Way

The Sri Lankan Ministry of National Coexistence, Dialogue, and Official Languages published the work “People of Sri Lanka” in 2017. In this comprehensive publication, 21 invited Sri Lankan scholars introduced 19 different people’s groups to public readers in English, mainly targeted at a growing number of foreign visitors in need of understanding the cultural diversity Sri Lanka has to offer. This paper will observe the presentation of these different groups of people, the role music and allied arts play in this context. Considering the non-scholarly design of the publication, a discussion of the role of music and allied arts has to be supplemented through additional analyses based on sources mentioned by the 21 participating scholars and their fragmented application of available knowledge. In result, this paper might help improve the way facts about groups of people, the way of grouping people, and the way of presenting these groupings are displayed to the world beyond South Asia. This fieldwork and literature guided investigation should also lead to suggestions for ethical principles in teaching and presenting of culturally different music practices within Sri Lanka, thus adding an example for other case studies.

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