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Humans and animals are affected by virulent nature of the above pathway. The critical pathway of trehalose biosynthesis involves consecutive reactions of trehalose phosphate synthase (TPS) and trehalose-6-phosphate phosphatase (TPP). Stress protectant molecule trehalose is an essential sugar in most organisms other than mammals. This confirms the tight binding between enzyme and leads which may pave way for the discovery of new generation drugs against TPP producing pathogenic microbes to manage diseases. Conclusionsīinding poses and distance measurement of TPP-phytochemical complexes of rutin, carpaine, stigmasterol, β-caryophyllene, and α-eudesmol reveals that the lead phytochemicals were in close proximity with most of the active site amino acids of region 3 (distance range from 1.796 to 2.747 A o). It has been found that during docking, phytochemical leads bind to active site region 3 of TPP sequences which coordinates Mg2+ and essential for catalysis. Docking studies of 3D model of TPP with 17 phytochemicals revealed most of them have good binding affinity to an enzyme with rutin exhibiting highest affinity (Binding energy of − 7 kcal/mole).
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Resultsīlast P and Clustal Omega phylogenetic analysis of TPP sequences were done for 12 organisms that indicate and confirm the presence of three conserved active site regions of known TPPs. Therefore, the present work is an approach to design new generation candidate drugs to inhibit TPP through in silico methods. Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA.Many of the pathogenic microbes use trehalose–6–phosphate phosphatase (TPP) enzymes for biosynthesis of sugar trehalose from trehalose–6–phosphate (T6P) in their pathway of infection and proliferation. aeruginosa PBP3 and open avenues for future design of inhibitors of this class of PBPs. Taken together, these structural, biochemical, and computational studies provide a molecular basis for recognition of P.
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Energetic analysis of tightly and loosely held computed hydration sites indicates protein desolvation effects contribute significantly to PBP3 binding, and analysis of hydration site energies allows rank ordering of the second-order acylation rate constants. This is also the first example of a siderophore-conjugated triazolone-linked monocarbam complexed with any PBP. Importantly, we have identified a novel conformation that is distinct to the high-molecular-weight class B PBP subfamily, which is identifiable by common features such as a hydrophobic aromatic wall formed by Tyr503, Tyr532, and Phe533 and the structural flexibility of Tyr409 flanked by two glycine residues. The structure of MC-1, a new siderophore-conjugated monocarbam complexed with PBP3 provides molecular insights for lead optimization. aeruginosa PBP3 is due to a distinct hydrophobic aromatic wall composed of Tyr503, Tyr532, and Phe533 interacting with the gem-dimethyl group. The well-known affinity of the monobactam aztreonam for P. These structures reveal a conformational rearrangement of Tyr532 and Phe533 and a ligand-induced conformational change of Tyr409 and Arg489. aeruginosa PBP3 with both novel and marketed β-lactams. Here we disclose the first high resolution cocrystal structures of the P. Penicillin-binding protein PBP3, a key therapeutic target, is an essential enzyme responsible for the final steps of peptidoglycan synthesis and is covalently inactivated by β-lactam antibiotics. Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen that causes nosocomial infections for which there are limited treatment options.