###### Abstract  
Mycobacterial fatty acid synthase type-I (FAS-I) has an important role in the de novo synthesis of fatty acids, which constitute a major component of the cell wall. The essentiality of FAS-I in the survival and growth of mycobacterium makes it an attractive drug target. However, targeted inhibitors against Mycobacterial FAS-I have not been reported yet. Recently, the structure of FAS-I from Mycobacterium tuberculosis was solved. Therefore, in a quest to find potential inhibitors against FAS-I, molecular docking-based virtual screening and molecular dynamics simulation were done. Subsequently, molecular dynamic simulations based on binding free energy calculations were done to gain insight into the predicted binding mode of putative hits. The detailed analysis resulted in the selection of four putative inhibitors. For compounds BTB14738, RH00608, SPB02705, and CD01000, binding free energy was calculated as \(-72.27\pm 12.63\), \(-68.06\pm 11.80\), \(-63.57\pm 12.22\), and \(-51.28\pm 13.74\) KJ/mol, respectively. These compounds are proposed to be promising pioneer hits. f +
Footnote †: journal: Medical Dynamics Simulation  
0000-0001-7700-0000][PERSON]; [PERSON]; [PERSON] Identification of Novel Inhibitors of Type-I Mycobacterium Tuberculosis Tuberculosis Fatty Acid Synthase Using Docking-Based Virtual Screening and Molecular Dynamics Simulation. 0000-0001-7700-0000][PERSON]; [PERSON]; [PERSON] Identification of Novel Inhibitors of Type-I Mycobacterium Tuberculosis Tuberculosis Tuberculosis Tuberculosis Surveillance  
with C26, resulting in the formation of mycolic acids [6; 7]. Furthermore, fatty acid synthesis has been reported to be essential in mycobacteria [10; 11]. The importance of fatty acid synthesis is also manifested by the use of drugs isoniaizid, ethambutol, and pyrazinamide in the current drug regimen, which are inhibitors of mycolic acid biosynthesis [12]. Isoniaizid and ethambutol targets enoyl reductase domain of the FAS-II system to inhibit mycolic acid synthesis and be used as first- and second-line drugs against TB. Pyrazinamide is being used as a first line drug and has a key role in shortening the drug regimen from nine to six months [13]. Moreover, analogs of pyrazinamide have been reported to target the FAS-I system of Mycobacterium [14; 15]. The role of mycolic acids in forming the cell wall and its key role in growth and survival of mycobacterium makes the FAS system an attractive drug target. Recently the structure of mycobacterial FAS-I was elucidated by [PERSON] et al. [16]. This has paved the way for structure based inhibitor identification against the mycobacterial FAS-I system. The receptor-inhibitor design is the spirit of any drug design process and the information of receptor-ligand complex can be channelized through many ways. Amongst them, virtual screening is one of the most commonly used to discover novel scaffolds and lead compounds [17; 18; 19]. Molecular docking is a popular choice to carry out the virtual screening and has proved its mettle in hit identification and lead optimization. Molecular docking has been successfully implemented to screen large compound libraries against the drug targets and identification of mechanism of action of known active compounds [20; 21; 22]. Docking methods have been used to screen in-house as well as commercial libraries. For example, virtual screening was successfully employed for the identification of antibacterial inhibitors against NAD synthetase [23]. Docking-based virtual screening was done to identify novel inhibitors against leishmaniasisial nucleoside diphosphate kinases [24]. In a recent study, docking-based screening was performed to identify potential inhibitors against isocitrate lyase of Mtb [25]. There are several other studies in which docking-based virtual screening has been successfully applied for the identification of novel inhibitors [26; 27; 28; 29; 30].