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Tuberculosis still persists a major challenge to healthcare system around the world. Increasing rates of morbidity, mortality and the reoccurrence of the resistant strains of the disease to accessible drugs/medications have made it crucial to search for a new therapy in term of novel and prominent hypothetical compound treat tuberculosis. Therefore...
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Context 1
... of 1,2,4-Triazole reported as antitubercular agents that were used in this study were acquired from the literature [8]. The general structure of analogues of 1, 2, 4-Triazole and the predicted and experimental activities of these compounds were presented in Figure 1 and Table 1 respectively. ...
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Acinetobacter baumannii is an opportunistic pathogen that seriously affects sick patients, causing Health Care Associated Infections (HCAI) such as pneumonia associated with mechanical ventilation, urinary tract infections and bacteremia, in recent years this bacterium has become a health problem worldwide, its isolation from infections present in...
Citations
... It saves cost, time and tends to be more effective than the traditional methods [9]. Such computational tools include molecular docking and Quantitative Structure Activity Relationship (QSAR) [10]. The knowledge of QSAR helps in establishing a relationship between various molecular structures of molecules and their experimental activities [11]. ...
... Molecular docking study was conducted between nine (9) boron pleuromutilin analogues (5,10,25,26,27,28,34,49 and 50) with better inhibitory activities, and the receptor (Wol Tl IF-1). The Tl IF-1 from wolbachia endosymbiont strain TRS of brugia malayi (protein receptor) was obtained from the protein data bank (PDB code: 2NCH). ...
... Molecules with poor drug-likeness and ADMET properties cannot progress into the preclinical research phase regardless of their high anti-proliferative activities or docking score [9]. Therefore, the physicochemical and ADMET properties of the selected compounds (5,10,25,26,27,28,34,49 and 50) were investigated using the online web servers; http://www.swissadme.ch/index.php and http://biosig.unimelb.edu.au/pkcsm ...
Lymphatic filariasis and Onchocerciasis remain one of the oldest known Neglected Tropical Diseases (NTD) caused by a group of parasitic filarial nematodes co-habiting with the bacteria wolbachia. One good treatment method focuses on the elimination of this symbiotic wolbachia. In this work, an in-silico study was conducted to investigate the anti-wolbachia activities of 52 boron-pleuromutilin analogues. The Density Functional Theory approach was employed to optimize the chemical structures of the various molecules while utilizing B3LYP with 6-31G⁄ basis set. Genetic Function Algorithm was used to generate four (4) models. Model 3 was found to best satisfy the conditions of the internal and external validation tests for a good QSAR model with R² =0.9151, R²adj =0.8939, Q²cv =0.8509, R²test =0.7516 and cRp² =0.7955. The result of standard docking performed between nine (9) selected ligands and the receptor Wol Tl IF-1 using iGEMDOCK showed binding energies ranging from -82.24 to -96.85kcal/mol. ADMET and drug-likeness properties prediction showed that Compound 49 has the best pharmacokinetic profile, with good pharmacological interactions, majorly, H-bonding and hydrophobic interactions with receptor's amino acids. This study has, therefore, provided useful information for future works pertaining design of new wolbachia inhibitors with improved anti-proliferative activity.
... Discovery of novel anti-tubercular inhibitors in the field of medical and pharmaceutical chemistry has been successfully established via computer-aided drug design. [9]. The advancement of this method has been expedited with definite resolutions during the optimization of chemical structures. ...
... Reference to observation and information recorded above in term of binding affinities and interaction types provide concrete confirmation that increase in the number of hydrogen bonds formation observed in ligand 17i, 17j and 17n accounts for their potency against DNA gyrase target [9,11,[16][17][18] compared to the template ligand 17 of quinoline ...
Background
Mycobacterium tuberculosis protein target (DNA gyrase) is a type II topoisomerase target present in all bacteria. The enzyme comprises of two subunits A and B. DNA binding domain is located in the subunits A while the catalysis and cleavage of two DNA strands occur in the subunits B using ATP hydrolysis. This enzyme has been reported to emerge in extensively drug resistant tuberculosis. Therefore this research aimed to design new potent compounds against the target and establish the analysis of protein–ligand binding interaction between the target and novel quinoline analogues via the application of in silico virtual screening to predict the inhibition binding affinities of the analogues.
Result
The docking results revealed that compound ID 17 with efficient inhibition activity has a noticeable binding affinity of −18.8 kcal/mol. Hence compound 17 was designated as the reference template to design novel fourteen compounds with higher binding affinities as a promising compounds.
Conclusion
Designed compound 17i, 17j and 17n with lead binding affinities among the designed compounds were observed with the most perceptible binding affinity which ranges from (−21.2 to −26.8) kcal/mol compared to low binding affinity (-5.8 kcal/mol) computed for ethambutol.
... The constructed model was subjected to various statistical tools to verify the potency of the model. Moreover, the threshold value for the internal and external have been laid to ascertain and affirm any kind of built model for validation as reported in Table 6 Roy, et al., 2013;Tropsha et al., 2003;Adeniji, 2020). Therefore, both the internal and external test reported in this work was compared and verified with the generally accepted threshold value to ascertain the potency and the robustness of the built model. ...
... With the Discovery Studio Visualizer software (V elizy-Villacoublay, France), all forms of solvent molecules, ligands and cofactors imported with the enzyme were removed in order to achieve good binding interactions between the enzyme (protein) and the ligands (molecules). Thereafter, the enzyme protein was saved in PDB format which is recognized by the Pyrx software and transformed as macromolecule Adeniji, 2020). Optimum conformation of the ligands (1,2,4 Triazole derivatives) at minima energy to enhance efficient binding interaction with the enzyme was achieved using Spartan version 14 software as an optimized tool utilizing DFT (B3LYP/631G Ã ). ...
... Optimum conformation of the ligands (1,2,4 Triazole derivatives) at minima energy to enhance efficient binding interaction with the enzyme was achieved using Spartan version 14 software as an optimized tool utilizing DFT (B3LYP/631G Ã ). Thereafter, all the ligands optimized were saved as PDB format which is also recognized by the Pyrx software and transformed as micro molecules Adeniji, 2020). In the Pyrx software, the docking interaction between the targeted enzyme and the protein were then computed to evaluate the binding affinities while the type of interaction such hydrogen bonding, electrostatic interaction and hydrophobic interaction were visualized and analyzed using the Discovery Studio Visualizer version 16 software (Adeniji, 2020;Adedirin et al., 2017;Ibrahim et al., 2020). ...
ABSTRACT
The increasing problem of multi-drug resistant-tuberculosis has focused attention on developing new drugs that are not only active against drug-resistant tuberculosis, but also shorten the lengthy therapy. Therefore, this work employs the application of modeling technique to predict the inhibition activities of some prominent compounds which been reported to be efficient against Mycobacterium tuberculosis. To accomplish the purpose of this work, multiple regression and genetic function approximation were adopted to create the model. The established model was swayed with topological descriptors; MATS7s, SpMin4_Bhv, TDB3v and RDF70v. More also, interactions between the compounds and the target protein ‘DNA gyrase’ were evaluated via molecular docking approach utilizing the PyRx and discovery studio simulation software. Based on the docking analysis, compound 20 has the most noticeable binding affinity of -16.5 kcal/mol. Therefore, compound 20 served as a reference structural template and insight to design fourteen novel hypothetical agents with more prominent anti-tubercular activities. More also, compound 20j was observed with the highest activity among the designed compounds with a prominent binding affinity of -24.3 kcal/mol. Therefore, this research recommends in-vivo, in-vitro screening and pharmacokinetic properties to be carried out in order to determine the toxicity of the designed compounds.
... A theoretical approach was employed to derive a QSAR model for predicting the activities of 1, 2, 4 Triazole analogues against Mycobacterium tuberculosis. Kennard-Stone algorithm approach employed [21,22] in this research was able to divide the studied compounds which comprises of 30 compounds into a training set of 21 compounds while the remaining 9 compound serve as the test set. The model generated was built on the basis of the training set while validation of the model was accessed by the test set ...
... The Person correlation coefficients calculated for the descriptors in the model was reported in Table 6. The low correlation coefficients that exist between each descriptor in the model imply that there exists no significant inter-correlation between each descriptor [21,22]. Statistical parameters calculated for the selected descriptors reported in Model 1 were repented in Table 6. ...
... While the N-H group triazolidine of the ligand also acts as hydrogen donor and formed two hydrogen bonds with GLN101 of the target. The hydrogen bond formation alongside with the hydrophobic interaction provides an evidence [21,22] that ligand 8 of the inhibitor compound is potent against DNA gyrase receptor. ...
Abstract
Time consumed and expenses in discovering and synthesizing new hypothetical drugs with improved biological activity have been a major challenge toward the treatment of multi-drug resistance strain Mycobacterium tuberculosis (TB). To solve the above problem, Quantitative structure activity relationship (QSAR) is a recent approach developed to discover a novel drug with a better biological against M. Tuberculosis. The developed model was validated through internal and external validation test. Molecular docking studies was as well carried for all the studied compounds in order to show the interactions and binding modes between the ligand and the receptor (DNA gyrase). The lead compound (compound 8) with higher anti-tubercular activity was observed with prominent binding affinity of -12.3 kcal/mol. Therefore, compound 8 could serve as a template structure to designed compounds with more efficient activities. The outcome of this research is recommended for pharmaceutical and medicinal chemists to design and synthesis more potent compounds with prominent anti-tubercular activities using the model designed in this study.
