ORIGINAL PAPER Molecular modeling studies of Fatty acyl-CoA synthetase (FadD13) from Mycobacterium tuberculosis—a potential target for the development of antitubercular drugs Nidhi Jatana & Sarvesh Jangid & Garima Khare & Anil K. Tyagi & Narayanan Latha # Springer-Verlag 2010 Abstract Tuberculosis (TB) is a global health problem and the situation has become more precarious due to the advent of HIV infections and continuous rise in the number of multi-drug resistant strains of Mycobacterium tuberculosis (M. tb). Biochemical studies on Fatty Acyl-CoA Synthe- tases (FadD13), one of the gene products of mymA operon, have provided insights into the involvement of this protein in the activation of fatty acids. Due to non-availability of the crystal structure of FadD13, we have employed in silico approaches to resolve and characterize the structure of this important protein of M. tb. A three dimensional model of M. tb FadD13 was predicted by a de novo structure prediction server that integrates fragment assembly with SimFold energy function. With the aid of molecular mechanics and dynamics methods, the final model was obtained and assessed subsequently for global and local accuracy by various assessment programs. With this model, a flexible docking study with the substrates was performed. Results of ligand interactions with key amino acids in the binding site are also summarized. The molecular model for the M. tb FadD13 obtained sheds light on the topographical features of the binding pocket of the protein and provides atomic insight into the possible modes of substrate recognition. The three-dimensional model of FadD13 presented here would be helpful in guiding both enzymatic studies as well as design of specific inhibitors. Keywords Docking . FadD13 . Molecular dynamics . M. tuberculosis . Structure prediction Introduction Tuberculosis (TB) remains one of the most important global health problems causing the loss of 2–3 million lives every year [1]. One-third of the world’ s population is asymptom- atically infected with Mycobacterium tuberculosis (M. tb), the etiologic agent of TB [2, 3]. Treatment of the active cases of TB includes simultaneous therapy with two or more of the frontline drugs: isoniazid, ethambutol, rifampi- cin and pyrazinamide [4]. Recent outbreaks of TB caused by multidrug-resistant (MDR) strains, mainly in the individuals infected with HIV, have created a precarious situation worldwide and have generated a significant interest in expanding the current programs of developing antitubercular drugs. Greater efforts are needed to investi- gate the molecular basis of pathogenicity and to develop high efficacy drugs against the key targets of M. tb. The determination of the M. tb genome sequence [5] has provided an enormous boost to these efforts and subsequent studies have attempted to identify genes that are likely to be required for the establishment and progression of TB leading to the identification of novel drug targets [6]. The rapid expansion of TB-related genomic data sources provides considerable opportunities to apply advanced computational analyses for the prediction of potential drug targets [7, 8]. TB Structural Genomics Consortium has significantly promoted these endeavors [9, 10]. Several proteins or pathways of M. tb have been demonstrated to be valid targets for drug design. The fatty acid biosynthesis pathway represents one such target for the development of new antimycobacterial agents [11, 12]. M. tb has ∼250 G. Khare : A. K. Tyagi Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, New Delhi 110021, India N. Jatana : S. Jangid : N. Latha (*) Bioinformatics Infrastructure Facility, Sri Venkateswara College, Benito Juarez Road, New Delhi 110021, India e-mail: lata@bic-svc.ac.in DOI 10.1007/s00894-010-0727-3 J Mol Model (2011) 17:301–313 Received: 28 January 2010 / Accepted: 20 April 2010 / Published online: 8 May 2010