ORIGINAL PAPER Identification of hotspot regions of MurB oxidoreductase enzyme using homology modeling, molecular dynamics and molecular docking techniques Vivek Kumar & Parameswaran Saravanan & Akanksha Arvind & C. Gopi Mohan Received: 13 April 2010 / Accepted: 18 June 2010 / Published online: 9 July 2010 # Springer-Verlag 2010 Abstract Despite the availability of effective chemothera- py and a moderately protective vaccine, new anti- tuberculosis agents are urgently needed to decrease the global incidence of tuberculosis (TB) disease. The MurB gene belongs to the bacterial cell wall biosynthesis pathway and is an essential drug target in Mycobacterium tubercu- losis (Mtb) that has no mammalian counterparts. Here, we present an integrated approach involving homology mod- eling, molecular dynamics and molecular docking studies on Mtb-MurB oxidoreductase enzyme. A homology model of Mtb-MurB enzyme was built for the first time in order to carry out structure-based inhibitor design. The accuracy of the model was validated using different techniques. The molecular docking study on this enzyme was undertaken using different classes of well known MurB inhibitors. Estimation of binding free energy by docking analysis indicated the importance of Tyr155, Arg156, Ser237, Asn241 and His304 residues within the Mtb-MurB binding pocket. Our computational analysis is in good agreement with experimental results of site-directed mutagenesis. The present study should therefore play a guiding role in the experimental design of Mtb-MurB inhibitors for in vitro/in vivo analysis. Keywords Mycobacterium tuberculosis MurB . Homology modeling . Molecular dynamics . Molecular docking Introduction Tuberculosis (TB) is a contagious-infectious disease caused mainly by Mycobacterium tuberculosis (Mtb). The resump- tion of TB, which is due mainly to the emergence of multidrug-resistant (MDR) and extensively drug-resistant strains of Mtb as well as HIV epidemics, has led to an increased need to understand the molecular mechanisms of drug action and drug resistance. These complicated issues need to be tackled by discovering novel compounds for TB therapy. The physiology of Mtb requires a high level of oxygen, and it usually establishes infection in the mammalian respiratory system [1]. In the lungs, Mtb are taken up by alveolar macrophages having high oxygen tension leading to accelerated growth of Mtb. It is quite difficult to stain such bacteria as they have an atypical waxy coating on the cell surface, comprised chiefly of mycolic acid, which makes the cells impervious to Gram staining. In 1882, Robert Koch, an esteemed scientist of his time, isolated and cultured Mtb from crushed tubercles. His experimental work identified the bacterium as the etiolog- ical agent of TB. He also developed staining methods for identification of the bacillus, and these techniques were subsequently improved on by the German doctor and bacteriologist Paul Ehrlich, whose method for the detection of the bacillus provided the basis for the development of the Ziehl-Nielsen acid-fast staining, which still is an important tool in TB therapy [2]. Mtb is a tenacious and remarkably successful pathogen that has latently infected one-third of the world’s popula- tion. Every year, 8 million new cases of TB appear and 2 million deaths occur [3]. The increasing emergence of drug-resistant TB and HIV infection, which compromises host defense and allows latent infection to reactivate or Electronic supplementary material The online version of this article (doi:10.1007/s00894-010-0788-3) contains supplementary material, which is available to authorized users. V. Kumar : P. Saravanan : A. Arvind : C. G. Mohan (*) Centre for Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar 160 062 Punjab, India e-mail: cmohan@niper.ac.in J Mol Model (2011) 17:939–953 DOI 10.1007/s00894-010-0788-3