ORIGINAL PAPER Computational evaluation of phytocompounds for combating drug resistant tuberculosis by multi-targeted therapy Sudharsana Sundarrajan 1 & Sajitha Lulu 1 & Mohanapriya Arumugam 1 Received: 4 July 2014 /Accepted: 11 August 2015 # Springer-Verlag Berlin Heidelberg 2015 Abstract The cell wall of Mycobacterium tuberculosis inter- acts with the host counterpart during the pathogenesis of tu- berculosis. L-rhamnosyl (L-Rha) residue, a linker connects the arabinogalactan and peptidoglycan moieties in the bacte- rial cell wall. The biosynthesis of L-rhamnose utilizes four successive enzymes RmlA, RmlB, RmlC and RmlD. Neither rhamnose nor the genes responsible for its synthesis are ob- served in humans. Thus, drugs inhibiting enzymes of this pathway are unlikely to interfere with metabolic pathways in humans. The adverse drug effects of first and second line drugs along with the development of multi-drug resistance tuberculosis have stimulated the research in search of new therapeutic drugs. Thus, it is attractive to hypothesize that inhibition of the biosynthesis of L-Rha would be lethal to the mycobacteria. Nature provides innumerable secondary metabolites with novel structural architectures with reported activity against M. tuberculosis. Combination of structure based virtual screening with physicochemical and pharmaco- kinetic studies against rhamnose pathway enzymes identified potential leads. The crucial screening studies recognized four phytocompounds butein, diospyrin, indicanine, and rumexneposide A with good binding affinity towards the rhamnose pathway proteins. Furthermore, the high through- put screening methods recognized butein, a secondary metabolite from Butea monosperma with strong anti- tubercular bioactive spectrum. Butein displayed promising anti-mycobacterial activity which is validated by Microplate alamar blue assay (MABA). The focus on novel agents like these phytocompounds which exhibit preference toward the successive enzymes of a single pathway can prevent the de- velopment of bacterial resistance. Keywords Mycobacterium . Phytocompounds . Rhamnose bio-synthesis . Virtual screening Introduction Tuberculosis remains a major global health issue caused by Mycobacterium tuberculosis. In 2012, there was an estimated 8.6 million incidents of tuberculosis (TB) around the world [1]. Multi drug resistant tuberculosis (MDR-TB) develops during treatment course and can readily infect patients with weak im- mune systems. MDR-TB became resistant to most powerful first-line anti-TB drugs like isoniazid (INH), rifampicin and major second-line drug groups such as fluoroquinolones and injectable drugs kanamycin, amikacin, and capreomycin [2]. Multi-drug regimens are now administered worldwide, offering a possible cure to the patients. Community-based treatment programs such as directly observed therapy short-course (DOTS) initiative, have shown considerable success in the treatment of MDR-TB in some parts of the world. However, adverse drug reaction and long therapy periods interrupt the treatment before completion, contributing to morbidity, drug resistance, and treatment failures [3]. M. tuberculosis develops resistance to anti-TB drugs by spontaneous mutation and the resulting resistant mutants are subsequently targeted by anti-TB drugs which render the drugs inactive. Additional mechanisms such as production Electronic supplementary material The online version of this article (doi:10.1007/s00894-015-2785-z) contains supplementary material, which is available to authorized users. * Mohanapriya Arumugam mohanapriyaa@vit.ac.in 1 Bioinformatics Division, School of Biosciences and Technology, Vellore Institute of Technology University, Vellore, Tamil Nadu, India 632014 J Mol Model (2015) 21:247 DOI 10.1007/s00894-015-2785-z