ORIGINAL RESEARCH Molecular docking studies on analogues of quercetin with D-alanine:D-alanine ligase of Helicobacter pylori Salam Pradeep Singh • Rocktotpal Konwarh • Bolin Kumar Konwar • Niranjan Karak Received: 5 March 2012 / Accepted: 17 August 2012 Ó Springer Science+Business Media, LLC 2012 Abstract Helicobacter pylori (Hp) is a human pathogen associated with myriad of diseases such as gastritis, peptic ulceration, piles and gastric cancer. The resistance of Hp against antimicrobial agents has increased just as that of other pathogens worldwide, thus emphasizing an urgent need for developing new antibacterial agents. The D-ala- nine:D-alanine ligase (Ddl, EC 6.3.2.4) has been considered as a putative antimicrobial drug target and a lot of inhibitor screening efforts have been made. Quercetin, a member of the flavonoids, characterized by a flavone nucleus com- posed of two benzene rings linked through a heterocyclic pyrone ring is reported to possess antibacterial activity against H. pylori Ddl (HpDdl) enzyme. In this milieu, we have performed molecular docking analysis of quercetin and its analogues at the active site of HpDdl. Some of the screened compounds showed better affinity and interaction with HpDdl enzyme. The docking analysis and absorption, distribution, metabolism and toxicity study forward few of them as plausible lead molecule or a novel class of drugs with enhanced pharmacological properties. Keywords Antimicrobial agent Á Antibacterial activity Á Flavonoids Á Molecular docking Introduction The elucidation of the link between Helicobacter pylori (Hp) and gastritis as well as ulceration of the stomach fetched J. Robin Warren and Barry J. Marshall the Nobel Prize in Medicine for the year 2005 (Sood, 2006). Since the discovery of the bacterium, the exact etiopathogenesis is continuously being updated. A perusal of recent reports unmasks the association of the bacterium with diverse extra-digestive morbidity, including insulin resistance syndrome (Polyzos et al., 2011) and numerous auto- immune disorders (Hasni et al., 2011) apart from adeno- carcinoma and gastric lymphoma. Furthermore, the oral cavity has also been proposed as a reservoir of Hp infection (Abdel-Monem et al., 2011). The risk intensifies as it has been hypothesized that the incidence of primary open- angle glaucoma may increase due to industrialization via quick transmission of Hp infection (Zavos et al., 2011). The gamut of enzymes catalyzing the synthesis of the peptidoglycan framework of the cell wall is a well- corroborated target for the antibacterial therapy (Wu et al., 2008a, b). D-alanine:D-alanine ligase (Ddl) synthesizes the terminal dipeptide, D-Ala:D-Ala, of the peptidoglycan precursor UDPMurNAc-pentapetide, a crucial building block involved in peptidoglycan cross-linking. Ala ana- logues (Neuhaus and Hammes, 1982), transition state analogues (Ellsworth et al., 1996) and allosteric inhibitor (Liu et al., 2006) are the reported inhibitors of Ddl. Recently, HpDdl has been identified as a new target for quercetin (3,3 0 ,4 0 ,5,7-pentahydroxyflavone) (Wu et al., 2008a). It is pertinent to mention that HpDdl keeps two conservatively substituted residues (Ile16 and Leu241) and two non-conserved residues (Leu308 and Tyr311) in the active region (that might partly contribute to the unique catalytic properties of the enzyme). Furthermore, a S. P. Singh (&) Á B. K. Konwar Bioinformatics Infrastructure Facility, Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur 784028, Assam, India e-mail: salampradeep@gmail.com R. Konwarh Á N. Karak (&) Advanced Polymer and Nanomaterial Laboratory, Department of Chemical Sciences, Tezpur University, Tezpur 784028, Assam, India e-mail: nkarak@tezu.ernet.in 123 Med Chem Res DOI 10.1007/s00044-012-0207-7 MEDICINAL CHEMISTR Y RESEARCH