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J Med Chem. 2017 Aug 24;60(16):6781-6827. doi: 10.1021/acs.jmedchem.7b00057. Epub 2017 May 5.

The Roles of Water in the Protein Matrix: A Largely Untapped Resource for Drug Discovery.

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Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino , Via Pietro Giuria 9, 10125 Torino, Italy.
Department of Medicinal Chemistry & Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University , Richmond, Virginia 23298-0540, United States.
CMD Bioscience , 5 Science Park, New Haven, Connecticut 06511, United States.
Dipartimento di Scienze degli Alimenti e del Farmaco, Laboratorio di Modellistica Molecolare, Università degli Studi di Parma , Parco Area delle Scienze 59/A, 43121 Parma, Italy.
Dipartimento di Scienze degli Alimenti e del Farmaco, Laboratorio di Biochimica, Università degli Studi di Parma , Parco Area delle Scienze 23/A, 43121 Parma, Italy.
Istituto di Biofisica, Consiglio Nazionale delle Ricerche , Via Moruzzi 1, 56124 Pisa, Italy.


The value of thoroughly understanding the thermodynamics specific to a drug discovery/design study is well known. Over the past decade, the crucial roles of water molecules in protein structure, function, and dynamics have also become increasingly appreciated. This Perspective explores water in the biological environment by adopting its point of view in such phenomena. The prevailing thermodynamic models of the past, where water was seen largely in terms of an entropic gain after its displacement by a ligand, are now known to be much too simplistic. We adopt a set of terminology that describes water molecules as being "hot" and "cold", which we have defined as being easy and difficult to displace, respectively. The basis of these designations, which involve both enthalpic and entropic water contributions, are explored in several classes of biomolecules and structural motifs. The hallmarks for characterizing water molecules are examined, and computational tools for evaluating water-centric thermodynamics are reviewed. This Perspective's summary features guidelines for exploiting water molecules in drug discovery.

[Indexed for MEDLINE]

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