Integration of ligand and structure based approaches for identification of novel MbtI inhibitors in Mycobacterium tuberculosis and molecular dynamics simulation studies

Mycobacterium tuberculosis is an obligate pathogen of mammals and is responsible for more than two million deaths annually. The ability to acquire iron from the extracellular environment is a key determinant of pathogenicity in mycobacteria. M. tuberculosis acquires iron exclusively through the siderophores. Several lines of evidence suggest that siderophores have a critical role in bacterial growth and virulence. Hence, in the present study, we have used a combined ligand and structure-based drug design approach for identification of novel inhibitors against salicylate synthase MbtI, a unique and essential enzyme for the biosynthesis of siderophores in M. tuberculosis. We have generated the ligand based and structure based pharmacophores and validated exhaustively. From the validation results it was found that GH (Goodness of Hit) scores for the selected ligand based and structure based pharmacophore models were 0.89 and 0.97, respectively, which indicate that the quality of the pharmacophore models are acceptable as GH value is >0.7. The validated pharmacophores were used for screening the ZINC database. A total of 73 hits, obtained through various insilico screening techniques, were further enriched to 17 hits using docking studies. Molecular dynamics simulations were carried out to compare the binding mode and stability of complexes of MbtI bound with substrate, known inhibitors, and three top ranked hits. The results obtained in this study gave assurance about the identified hits as prospective inhibitors of MbtI.     

In silico and in vitro screening to identify structurally diverse non-azole CYP51 inhibitors as potent antifungal agent

The problem of resistance to azole class of antifungals is a serious cause of concern to the medical fraternity and thus there is an urgent need to identify non-azole scaffolds with high affinity for lanosterol 14α-demethylase (CYP51). In view of this we have attempted to identify novel non-azole CYP51 inhibitors through the application of pharmacophore based virtual screening and in vitro evaluation. A rigorously validated pharmacophore model comprising of 2 hydrogen bond acceptor and 2 hydrophobic features has been developed and used to mine NCI database. Out of 265 retrieved hits, NSC 1215 and 1520 have been chosen on the basis of Lipinski’s rule of five, fit and estimated values. Both the hits were docked into the active site of CYP51. In view of high fit value and CDocker score, NSC 1215 and 1520 have been subjected to in vitro microbiological assay. The result reveals that NSC 1215 and 1520 are active against Candida albicans, Candida parapsilosis, Candida tropicalis, and Aspergillus niger. In addition to this the absorption characteristics of both the hits have also been determined using the rat sac technique and permeation in order of NSC 1520 > NSC 1215 has been observed.     

In silico study of subtilisin-like protease 1 (SUB1) from different Plasmodium species in complex with peptidyl-difluorostatones and characterization of potent pan-SUB1 inhibitors

Plasmodium falciparum subtilisin-like protease 1 (SUB1) is a novel target for the development of innovative antimalarials. We recently described the first potent difluorostatone-based inhibitors of the enzyme ((4S)-(N-((N-acetyl-l-lysyl)-l-isoleucyl-l-threonyl-l-alanyl)-2,2-difluoro-3-oxo-4-aminopentanoyl)glycine (1) and (4S)-(N-((N-acetyl-l-isoleucyl)-l-threonyl-l-alanylamino)-2,2-difluoro-3-oxo-4-aminopentanoyl)glycine (2)). As a continuation of our efforts towards the definition of the molecular determinants of enzyme-inhibitor interaction, we herein propose the first comprehensive computational investigation of the SUB1 catalytic core from six different Plasmodium species, using homology modeling and molecular docking approaches. Investigation of the differences in the binding sites as well as the interactions of our inhibitors 1,2 with all SUB1 orthologues, allowed us to highlight the structurally relevant regions of the enzyme that could be targeted for developing pan-SUB1 inhibitors. According to our in silico predictions, compounds 1,2 have been demonstrated to be potent inhibitors of SUB1 from all three major clinically relevant Plasmodium species (P. falciparum, P. vivax, and P. knowlesi). We next derived multiple structure-based pharmacophore models that were combined in an inclusive pan-SUB1 pharmacophore (SUB1-PHA). This latter was validated by applying in silico methods, showing that it may be useful for the future development of potent antimalarial agents.     

Virtual screening of eighteen million compounds against dengue virus: Combined molecular docking and molecular dynamics simulations study

Dengue virus is a major issue of tropical and sub-tropical regions. Dengue virus has been the cause behind the major alarming epidemics in the history with mass causalities from the decades. Unavailability of on-shelf drugs for the prevention of further proliferation of virus inside the human body results in immense number of deaths each year. This issue necessitates the design of novel anti-dengue drug. The protease enzyme pathway is the critical target for drug design due to its significance in the replication, survival and other cellular activities of dengue virus. Therefore, approximately eighteen million compounds from the ZINC database have been virtually screened against nonstructural protein 3 (NS3). The incremental construction algorithm of Glide docking program has been used with its features high throughput virtual screening (HTVS), standard precision (SP), extra precision (XP) and in combination of Prime module, induced fit docking (IFD) approach has also been applied. Five top-ranked compounds were then selected from the IFD results with better predicted binding energies with the catalytic triad residues (His51, Asp75, and Ser135) that may act as potential inhibitors for the underlying target protease enzyme. The top-ranked compounds ZINC95518765, ZINC44921800, ZINC71917414, ZINC39500661, ZINC36681949 have shown the predicted binding energies of −7.55, −7.36, −8.04, −8.41, −9.18 kcal/mol, respectively, forming binding interactions with three catalytically important amino acids. Top-docking poses of compounds are then used in molecular dynamics (MD) simulations. In computational studies, our proposed compounds confirm promising results against all the four serotypes of dengue virus, strengthening the opportunity of these compounds to work as potential on-shelf drugs against dengue virus. Further experimentation on the proposed compounds can result in development of strong inhibitors.     

Impact of multimodal feedback on simulated ergonomic measurements in a virtual environment: A case study with manufacturing workers

The purpose of this study was to evaluate the impact of multimodal feedback on ergonomic measurements in a virtual environment (VE) for a typical simulated drilling task. In total, sixty male manufacturing industry workers were divided into five groups. One group performed the working task in a real environment (RE), and ergonomic measurements for this group were used as the baseline for evaluation. The other four groups performed the same task in a virtual environment with different feedback treatments (visual with or without auditory and/or tactile feedback). Five indices – task completion time, maximum force capacity reduction, body part discomfort, rated perceived exertion, and rated task difficulty – were used to evaluate the measurements of each of the four treatments in VE in comparison to the baseline group in RE. The results indicate that the five indices for each of the four treatment groups were significantly higher than those of the RE group. Moreover, the indices of the visual‐only group were significantly higher than those of the other three groups with auditory and/or tactile feedback treatments. The findings of this study can provide a guideline for ergonomic evaluations of work designs in VE and for establishing a virtual reality simulation system. © 2011 Wiley Periodicals, Inc.     

Modeling and analysis of pumps in a wastewater treatment plant: A data-mining approach

A data-mining approach is proposed to model a pumping system in a wastewater treatment plant. Two parameters, energy consumption and wastewater flow rate after the pumping system, are used to evaluate the performance of 27 scenarios while the pump was operating. Five data-mining algorithms are applied to identify the relationships between the outputs (energy consumption and wastewater flow rate) and the inputs (elevation level of the wet well and the speed of the pumps). The accuracy of the flow rate and energy consumption models exceeded 90%. The derived models are deployed to optimize the pump system. The computational results obtained with the proposed models are discussed.     

Factors influencing the perceived usability of wearable chair exoskeleton with market segmentation: A structural equation modeling and K-Means Clustering approach

The sudden implementation of work-from-home setup has caused the rise of sedentary position among employees which led to an increase in development or worsening of musculoskeletal disorders. To help mitigate this problem, wearable assistive devices such as wearable chairs have been argued to be beneficial. Several studies have expounded on the benefit of using this, however little to no available device is yet present in the Philippines. To which, businesses and developers could capitalize on this aspect. This study examined the perceived usability of wearable chair exoskeleton in the Philippines by integrating the Unified Theory of Acceptance and Use of Technology (UTAUT2) and System Usability Scale (SUS). A questionnaire was developed and distributed to 365 residents in the Philippines to measure the factors and their relationship to perceived usability accurately. Indicators and measures used in the questionnaire were derived from existing literature on technology acceptance and usability evaluation. Partial least squares structural equation modeling (PLS-SEM) was used for this study. Results revealed that perceived usability was significantly influenced by usage behavior. At the same time, habit, hedonic motivation, and performance expectancy significantly influenced the behavioral intention of the wearable chair exoskeleton. K-Means clustering was also utilized to identify clusters of target users of the wearable chair in the country, such as high-value customers, core customers, and low-value customers. Results indicated that demographic factors such as females, 30 years old and below, earning Php45,000 and above monthly, and living in a city are highly likely to utilize the product. The findings of this study can be applied and extended as a theoretical framework for future researchers of consumer behavior and exoskeleton developers for enhancing the innovation and usability of this new technology. This study may also be used and capitalized by investors to strategize the development and marketing of the exoskeletons among industrial and teleworkers worldwide.     

A novel classification method: A hybrid approach based on extension of the UTADIS with polynomial and PSO-GA algorithm

In this study, a new multi-criteria classification technique for nominal and ordinal groups is developed by expanding the UTilites Additives DIScriminantes (UTADIS) method with a polynomial of degree T which is used as the utility function rather than using a piecewise linear function as an approximation of the utility function of each attribute. We called this method as PUTADIS. The objective is calculating the coefficients of the polynomial and the threshold limit of classes and weight of attributes such that it minimizes the number of misclassification error. Estimation of unknown parameters of the problem is calculated by using a hybrid algorithm which is a combination of particle swarm optimization algorithm (PSO) and Genetic Algorithm (GA). The results obtained by implementing the model on different datasets and comparing its performance with other previous methods show the high efficiency of the proposed method.     

A priori molecular descriptors in QSAR: a case of HIV-1 protease inhibitors. II. Molecular graphics and modeling

Molecular graphics and modeling methods illustrated the chemical background of the a priori approach from part I, and visualized steric and electronic enzyme-inhibitor relationships at qualitative and quantitative level for 34 and its derivatives. The enzyme-inhibitor electron density overlap occurs at 1.5–5.5 Å cut-off distance, beyond van der Waals radii. Derivatives of 34 exhibit linear relationships between biological activity, molecular size and number of intermolecular interactions.     

Unveiling and taming liabilities of aspects in the presence of exceptions: A static analysis based approach

As aspects extend or replace existing functionality at specific join points in the code, their behavior may raise new exceptions, which can flow through the program execution in unexpected ways. Assuring the reliability of exception handling code in aspect-oriented (AO) systems is a challenging task. Testing the exception handling code is inherently difficult, since it is tricky to provoke all exceptions during tests, and the large number of different exceptions that can happen in a system may lead to the test-case explosion problem. Moreover, we have observed that some properties of AO programming (e.g., quantification, obliviousness) may conflict with characteristics of exception handling mechanisms, exacerbating existing problems (e.g., uncaught exceptions). The lack of verification approaches for exception handling code in AO systems stimulated the present work. This work presents a verification approach based on a static analysis tool, called SAFE, to check the reliability of exception handling code in AspectJ programs. We evaluated the effectiveness and feasibility of our approach in two complementary ways (i) by investigating if the SAFE tool is precise enough to uncover exception flow information and (ii) by applying the approach to three medium-sized ApectJ systems from different application domains.