scholarly journals Combinatorial Design to Decipher Novel Lead Molecule against Mycobacterium tuberculosis

2021 ◽  
Vol 11 (5) ◽  
pp. 12993-13004
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Molecular Docking ◽  
Sustainable Growth ◽  
Combinatorial Design ◽  
Inhibition Mechanism ◽  
The Novel ◽  
Combinatorial Approach ◽  
Virtual Library ◽  
Substrate Analogs ◽  
Semialdehyde Dehydrogenase

Aspartate-semialdehyde dehydrogenase (ASADH) of DAP/lysine pathway plays a crucial role in sustainable growth and pathogenicity of Mycobacterium tuberculosis (Mtb) via reductive dephosphorylation of the β-aspartyl phosphate (AP). Inhibition of ASADH through different lead molecules has been gaining high impetus due to its indispensable role in the pathogen’s survival. In the present study, we aimed to decipher the novel lead molecule against Mtb. The AP, a substrate of the DAP/lysine pathway, was used as a template to design new lead molecules to advance the understanding of the molecular inhibition mechanism of Mtb-ASADH. Monodentate and bidentate groups at three different substitution sites of AP were considered to generate a virtual library of new molecules using the combinatorial approach of the LeadGrow module of the VLifeMDS package. These substrate analogs were sifted through ADRXWS drug-likeness descriptors of the module above. Multi-scoring docking was achieved using Biopredicta, Molecular Virtual Docker, and AutoDock Tools. The adopted combinatorial approach yielded 6000 new molecules that reduced to 4979 plausible hits after lead-like filtration. The post-analysis of ADMET and molecular docking exhibited two pro-lead molecules, namely AP0600 and AP0639. The study delineates the substantial understanding of the Mtb-ASADH inhibition mechanism that would undoubtedly accelerate the pace of antitubercular design, thereby gaining more in-depth knowledge to eradicate tuberculosis across the globe.

The Antiviral and Antimalarial Drug Repurposing in Quest of Chemotherapeutics to Combat COVID-19 Utilizing Structure-Based Molecular Docking

2020 ◽  
Vol 23 ◽  
Author(s):  
Sisir Nandi ◽  
Mohit Kumar ◽  
Mridula Saxena ◽  
Anil Kumar Saxena
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Drug Repurposing ◽  
Clinical Settings ◽  
The Novel ◽  
In Silico Docking ◽  
Biochemical Mechanisms ◽  
Novel Coronavirus ◽  
In Silico Molecular Docking

Background: The novel coronavirus disease (COVID-19) is caused by a new strain (SARS-CoV-2) erupted in 2019. Nowadays, it is a great threat that claims uncountable lives worldwide. There is no specific chemotherapeutics developed yet to combat COVID-19. Therefore, scientists have been devoted in the quest of the medicine that can cure COVID- 19. Objective: Existing antivirals such as ASC09/ritonavir, lopinavir/ritonavir with or without umifenovir in combination with antimalarial chloroquine or hydroxychloroquine have been repurposed to fight the current coronavirus epidemic. But exact biochemical mechanisms of these drugs towards COVID-19 have not been discovered to date. Method: In-silico molecular docking can predict the mode of binding to sort out the existing chemotherapeutics having a potential affinity towards inhibition of the COVID-19 target. An attempt has been made in the present work to carry out docking analyses of 34 drugs including antivirals and antimalarials to explain explicitly the mode of interactions of these ligands towards the COVID-19protease target. Results: 13 compounds having good binding affinity have been predicted towards protease binding inhibition of COVID-19. Conclusion: Our in silico docking results have been confirmed by current reports from clinical settings through the citation of suitable experimental in vitro data available in the published literature.

In Silico Appraisal, Synthesis, Antibacterial Screening and DNA Cleavage for 1,2,5-thiadiazole Derivative

2019 ◽  
Vol 15 (5) ◽  
pp. 445-455 ◽  
Author(s):  
Suraj N. Mali ◽  
Sudhir Sawant ◽  
Hemchandra K. Chaudhari ◽  
Mustapha C. Mandewale
Keyword(s):  
Molecular Docking ◽  
Dna Cleavage ◽  
In Silico ◽  
Oral Absorption ◽  
Inhibition Mechanism ◽  
Hydrogen Binding ◽  
Docking Score ◽  
Antibacterial Screening ◽  
Mycobacteria Tuberculosis

Background: : Thiadiazole not only acts as “hydrogen binding domain” and “two-electron donor system” but also as constrained pharmacophore. Methods:: The maleate salt of 2-((2-hydroxy-3-((4-morpholino-1, 2,5-thiadiazol-3-yl) oxy) propyl) amino)- 2-methylpropan-1-ol (TML-Hydroxy)(4) has been synthesized. This methodology involves preparation of 4-morpholino-1, 2,5-thiadiazol-3-ol by hydroxylation of 4-(4-chloro-1, 2,5-thiadiazol-3-yl) morpholine followed by condensation with 2-(chloromethyl) oxirane to afford 4-(4-(oxiran-2-ylmethoxy)-1,2,5-thiadiazol- 3-yl) morpholine. Oxirane ring of this compound was opened by treating with 2-amino-2-methyl propan-1- ol to afford the target compound TML-Hydroxy. Structures of the synthesized compounds have been elucidated by NMR, MASS, FTIR spectroscopy. Results: : The DSC study clearly showed that the compound 4-maleate salt is crystalline in nature. In vitro antibacterial inhibition and little potential for DNA cleavage of the compound 4 were explored. We extended our study to explore the inhibition mechanism by conducting molecular docking, ADMET and molecular dynamics analysis by using Schrödinger. The molecular docking for compound 4 showed better interactions with target 3IVX with docking score of -8.508 kcal/mol with respect to standard ciprofloxacin (docking score= -3.879 kcal/mol). TML-Hydroxy was obtained in silico as non-carcinogenic and non-AMES toxic with good percent human oral absorption profile (69.639%). TML-Hydroxy showed the moderate inhibition against Mycobacteria tuberculosis with MIC 25.00 μg/mL as well as moderate inhibition against S. aureus, Bacillus sps, K. Pneumoniae and E. coli species. Conclusion: : In view of the importance of the 1,2,5-thiadiazole moiety involved, this study would pave the way for future development of more effective analogs for applications in medicinal field.

scholarly journals In Vitro Activities of the Novel Oxazolidinones DA-7867 and DA-7157 against Rapidly and Slowly Growing Mycobacteria

2006 ◽  
Vol 50 (12) ◽  
pp. 4027-4029 ◽  
Author(s):  
Lucio Vera-Cabrera ◽  
Barbara A. Brown-Elliott ◽  
Richard J. Wallace ◽  
Jorge Ocampo-Candiani ◽  
Oliverio Welsh ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Clinical Isolates ◽  
Nontuberculous Mycobacterium ◽  
The Novel ◽  
Broth Microdilution ◽  
Reference Species ◽  
Microdilution Method ◽  
Broth Microdilution Method ◽  
Aerobic Actinomycetes

ABSTRACT DA-7867 and DA-7157 are oxazolidinones active against pathogenic aerobic actinomycetes including Nocardia spp. and Mycobacterium tuberculosis. However, the activity of these drugs against nontuberculous mycobacterium (NTM) species is not known. In this work, we compared the susceptibilities of 122 clinical isolates and 29 reference species of both rapidly growing and slowly growing mycobacteria to linezolid, DA-7867, and DA-7157 by the broth microdilution method. The MICs for 50 and 90% of the strains tested (MIC50s and MIC90s, respectively) of DA-7867 and DA-7157 were lower than those of linezolid. In all of the cases, a MIC90 of <8 μg/ml was observed for all of the species tested in both groups of NTM. For M. kansasii and M. marinum isolates, the MIC90s of both DA-7867 and DA-7157 were less than 0.5 μg/ml. These results demonstrate the potential of these compounds to treat NTM infections.

scholarly journals Insight to pyrazinamide resistance in Mycobacterium tuberculosis by molecular docking

2009 ◽  
Vol 4 (1) ◽  
pp. 24-29 ◽  
Author(s):  
A. Nusrath Unissa ◽  
N. Selvakumar ◽  
Sameer Hassan
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Molecular Docking
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