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The Open Form Inducer Approach for Structure-Based Drug Design.

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|November 29, 2016
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Summary

A novel method was developed to obtain the open form (OF) structure of drug targets a priori, accelerating the design of potent inhibitors for challenging proteins like Trypanosoma cruzi dihydroorotate dehydrogenase (TcDHODH). This approach enables drug discovery for diseases with difficult molecular targets.

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Area of Science:

  • Structural biology
  • Drug discovery
  • Parasitology

Background:

  • Conventional methods often determine drug target structures post-hoc, delaying inhibitor development.
  • Trypanosoma cruzi dihydroorotate dehydrogenase (TcDHODH) presents challenges due to its small active site and monomeric functionality, hindering traditional drug design.
  • Developing methods to obtain target structures a priori is crucial for efficient drug development.

Purpose of the Study:

  • To develop and validate a novel a priori approach for obtaining the open form (OF) structure of TcDHODH.
  • To demonstrate the utility of this approach in designing potent and selective inhibitors against TcDHODH.
  • To establish a strategy applicable to other challenging drug targets with small active sites.

Main Methods:

  • In silico prediction of an 'OF inducer' molecule designed to bind TcDHODH.
  • Inducing steric repulsion to force the flexible regions near the active site, thereby opening the target structure.
  • Co-crystallization of TcDHODH with the predicted OF inducer and subsequent structure determination.
  • Design and structural analysis of inhibitors based on the obtained OF structure.

Main Results:

  • Successful prediction and crystallization of TcDHODH in complex with an OF inducer, yielding the OF structure a priori.
  • Determination of fourteen co-crystal structures of TcDHODH with newly designed potent and selective inhibitors.
  • Proof-of-concept for the 'OF inducer' strategy in drug design against difficult targets.

Conclusions:

  • The developed a priori approach effectively obtains the open form structure of TcDHODH, overcoming limitations of conventional methods.
  • This strategy facilitates the design of potent and selective inhibitors for TcDHODH, a key target in Chagas disease.
  • The approach holds significant potential for advancing drug discovery against challenging protein targets and exploring protein conformational dynamics.