Background: 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. Therefore, the present work is an approach to design new generation candidate drugs to inhibit TPP through in silico methods. Results: Blast 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. 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). 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. Conclusions: Binding 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). 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.

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