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Title: A new approach to the use of water molecules in computer-aided drug design
Author: García Sosa, Alfonso Tlatoani
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2004
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The present dissertation describes work conducted on analysing water molecules in the crystal structures of selected enzymes, the evaluation of several physicochemical properties of these waters, as well as the development of methods derived from these studies for their use as a tool in designing ligands for enzymes. Water molecules are a crucial part of the medium in which enzymes function. This is exemplified even further by their observation in crystal structures interacting with both ligands and enzymes. This has prompted their role as crucial features of molecular recognition, binding specificity, as well as potency of ligands. Therefore, ways of making use of their features are important in the development of drug design methods. A survey was conducted in order to describe the patterns of water molecules in the binding sites of crystal structures of therapeutically relevant enzymes. A multivariate statistical analysis was then performed on the resulting properties and from these, new functions and computer programs were developed in order to discern between different water molecules and hence provide reliability in water molecule inclusion or knowledge of their features for inhibitor design strategies. A further confirmation of these discerning functions is presented as provided by a ligand-based method used in conjunction with structure-based approaches to discerning important water molecules interacting with both ligands and enzymes. An exploration into the use of these rules or functions applied to two specific cases of structure. generation observing effects of including, targeting or neglecting predicted important water molecules is presented. Finally, molecular dynamics techniques such as free energy perturbations are introduced as tools to estimate energetic values for strategies of inclusion or targeting of water molecules in enzyme binding sites.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral