TY - ABST

T1 - LEGO-inspired drug design: Discovery of novel fungal Plasma membrane H+-ATPase (Pma1) inhibitors from small molecule libraries: An introduction of HFSA-SBS_DOS-RD strategy in drug discovery.

AU - Tung, Truong Thanh

AU - Dao, Trong Tuan

AU - Palmgren, Michael B.

AU - Fuglsang, Anja T.

AU - Christensen, Soeren B.

AU - Nielsen, John.

PY - 2017/4/2

Y1 - 2017/4/2

N2 - Fungal plasma membrane H+-ATPase (Pma1) has recently emerged as a potential target for the discovery of new antifungal agents. This p-type pump which localized on the surface of fungal cells plays a crucial role in many physiol. functions and processes inside the cell. Esp., by pumping proton to extracellular, this enzyme generates a transmembrane electrochem. gradient, as a consequence, fungi can uptake nutrients by secondary transport systems. Until now, only low resoln. of protein structure has been reported, and notably there a no report of co-crystal structure of Pma1 with inhibitors. Therefore, we have identified the need for small mol. library of high quality for targeting Pma1. The LEGO-inspired hypothesis encouraged us to first develop new strategy from the combination of hypothesis-based fragment selection and assembly (HFSA), specific biol. relevance scaffold based diversity-oriented synthesis (SBS_DOS) and rational design (RD), so called HFSA-SBS_DOS-RD strategy in drug discovery and development process. Using HFSA-SBS_DOS-RD, our group successfully designed, synthesized, and performed SAR studies of novel compds. potent Pma1 inhibitors. An expeditious, high yield and scalable microwave-assisted synthesis was developed and applied for synthesis of library compds. To our delight, ours compd. libraries were able to inhibit Pma1 activity and growth inhibitory activity of C. albican and S. cerevisiae revealed the most promising example for future development of antifungal drugs on this target. [on SciFinder(R)]

AB - Fungal plasma membrane H+-ATPase (Pma1) has recently emerged as a potential target for the discovery of new antifungal agents. This p-type pump which localized on the surface of fungal cells plays a crucial role in many physiol. functions and processes inside the cell. Esp., by pumping proton to extracellular, this enzyme generates a transmembrane electrochem. gradient, as a consequence, fungi can uptake nutrients by secondary transport systems. Until now, only low resoln. of protein structure has been reported, and notably there a no report of co-crystal structure of Pma1 with inhibitors. Therefore, we have identified the need for small mol. library of high quality for targeting Pma1. The LEGO-inspired hypothesis encouraged us to first develop new strategy from the combination of hypothesis-based fragment selection and assembly (HFSA), specific biol. relevance scaffold based diversity-oriented synthesis (SBS_DOS) and rational design (RD), so called HFSA-SBS_DOS-RD strategy in drug discovery and development process. Using HFSA-SBS_DOS-RD, our group successfully designed, synthesized, and performed SAR studies of novel compds. potent Pma1 inhibitors. An expeditious, high yield and scalable microwave-assisted synthesis was developed and applied for synthesis of library compds. To our delight, ours compd. libraries were able to inhibit Pma1 activity and growth inhibitory activity of C. albican and S. cerevisiae revealed the most promising example for future development of antifungal drugs on this target. [on SciFinder(R)]

M3 - Conference abstract for conference

T2 - 253rd American Chemical Society National Meeting & Exposition

Y2 - 2 April 2017 through 6 April 2017

ER -