title: Protein-protein interaction and molecular dynamics analysis for identification of novel inhibitors in Burkholderia cepacia GG4.
abstract: The lack of complete treatments and appearance of multiple drug-resistance strains of Burkholderia cepacia complex (Bcc) are causing an increased risk of lung infections in cystic fibrosis patients. Bcc infection is a big risk to human health and demands an urgent need to identify new therapeutics against these bacteria. Network biology has emerged as one of the prospective hope in identifying novel drug targets and hits. We have applied protein-protein interaction methodology to identify new drug-target candidates (orthologs) in Burkhloderia cepacia GG4, which is an important strain for studying the quorum-sensing phenomena. An evolutionary based ortholog mapping approach has been applied for generating the large scale protein-protein interactions in B. Cepacia. As a case study, one of the identified drug targets; GEM_3202, a NH (3)-dependent NAD synthetase protein has been studied and the potential ligand molecules were screened using the ZINC database. The three dimensional structure (NH (3)-dependent NAD synthetase protein) has been predicted from MODELLERv9.11 tool using multiple PDB templates such as 3DPI, 2PZ8 and 1NSY with sequence identity of 76%, 50% and 50% respectively. The structure has been validated with Ramachandaran plot having 100% residues of NadE in allowed region and overall quality factor of 81.75 using ERRAT tool. High throughput screening and Vina resulted in two potential hits against NadE such as ZINC83103551 and ZINC38008121. These molecules showed lowest binding energy of -5.7kcalmol-1and high stability in the binding pockets during molecular dynamics simulation analysis. The similar approach for target identification could be applied for clinical strains of other pathogenic microbes.
authors: Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector-62, Noida, Uttar Pradesh, 201307, India.
authors: Money
authors: M
authors: Gupta
authors: Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector-62, Noida, Uttar Pradesh, 201307, India.
authors: Rashi
authors: R
authors: Chauhan
authors: Department of Computer Science and Engineering, Indian Institute of Technology Delhi, New Delhi, 110016, India.
authors: Yamuna
authors: Y
authors: Prasad
authors: Department of Biotechnology (DBT), Ministry of Science & Technology, New Delhi-110003, India.
authors: Gulshan
authors: G
authors: Wadhwa
authors: Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector-62, Noida, Uttar Pradesh, 201307, India. Electronic address: ckj522@yahoo.com.
authors: Chakresh Kumar
authors: CK
authors: Jain
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D016956:Burkholderia cepacia / Q000187:drug effects*; D056004:Molecular Dynamics Simulation; D011485:Protein Binding
chemical_list: D000900:Anti-Bacterial Agents
keywords: B. cepacia; Molecular dynamics; Multiple-drug resistance; NadE; Ortholog mapping