Molecular modeling studies and anti-TB activity of trisubstituted indolizine analogues; molecular docking and dynamic inputs |
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Authors: | Mohammed A. Khedr Melendhran Pillay Sandeep Chandrashekharappa Deepak Chopra Bandar E. Aldhubiab Mahesh Attimarad |
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Affiliation: | 1. Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Kingdom of Saudi Arabia;2. Department of Microbiology, National Health Laboratory Services, KZN Academic Complex, Inkosi Albert Luthuli Central Hospital, Durban 4001, South Africa;3. Institute for Stem Cell Biology and Regenerative Medicine, NCBS, TIFR, GKVK, Bellary Road, Bangalore 560 065, India;4. Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal By-pass Road, Bhauri, Bhopal 462 066, India |
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Abstract: | A series of trisubstituted indolizine analogues has been designed as a result of a fragment-based approach to target the inhibition of mycobacterial enoyl-acyl carrier protein reductase. Anti-tuberculosis (TB) screening of the characterized compounds by a resazurin microplate assay method revealed that ethyl group at second position of indolizine nucleus exhibited activity against susceptible and multidrug-resistant strains of Mycobacterium tuberculosis at concentration of 5.5 and 11.3 μg/mL, respectively. A molecular docking study was also conducted to evaluate the stability of the active compounds, and compound with ethyl substitution at second position of indolizine nucleus showed the highest free binding energy of ΔG ?24.11 (kcal/mol), a low clash score of 3.04, and high lipo score of ?13.33. Indolizine analog with ethyl substitution at second position demonstrated Molecular Mechanics/Generalized Born Surface Area (?23.85 kcal/mol). Two molecular dynamics studies were computed (100 ps and 50 ns) to calculate the relationship between the potential and kinetic energies of the active anti-TB compound with time and temperature. The discovery of this lead may have a positive impact on anti-TB drug discovery. |
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Keywords: | anti-TB indolizines docking studies dynamics studies single crystal X-ray studies |
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