Bioinformatics With Biological Sense

In conclusion, the molecular mechanism of binding and activation is reappraised by analysis of structure-function relationships in respect of receptor sequences and phylogenetic relationships. The wealth and superfluity of GPCR data bedevil holistic appreciation and contemplation of a universal activation mechanism for 7TMRs. The general lack of amenability of 7TMRs to manipulation and to structural determination efforts are recurrent themes throughout this volume on GPCRs in drug discovery, requiring highly concentrated effort and many ingenious approaches.

Bioinformatic analyses are less constrained and can evaluate virtual scenarios and exploit comparative information to glean new insights and comprehension. Despite this freedom, analyses can be too restrictive when developed from the safety of a particular model and may simply bolster the status quo, precluding the discovery of new models and failing to question established paradigms. Analyses may also be too rarified and fail to acknowledge the murkiness and non-ideal state of the biological condition, neglecting physiological context, the contributions of ligand pharmacokinetics and dynamics, and the relevance of general evolutionary (phylogeny) and individual developmental (ontogeny) constraints.

Just as chemoinformatics and molecular visualization depend on chemical sense, the execution of a computational biology approach that attempts to integrate all relevant information in a biologically holistic and comprehensive way, with biology and not computational tractability as the final arbiter, is bioinformatics with biological sense. Biological sense would suggest that the chameleon reactivities of cysteine residues, ranging from the textbook definitions of "simply" structural to the highly reactive chemistries of enzymatic activity and redox modulation of protein function, is a potential that nature cannot fail to exploit. By knowing the mechanism of receptor activation, drug discovery initiatives can also exploit this potential.

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