Structure-based drug discovery has played an important role in medicinal chemistry, 1 beginning nearly when the first X-ray crystal structure of the myoglobin and hemoglobin proteins at near-atomic resolution were described by Perutz, Kendrew and colleagues. 2-5 Even though only static structures were (and still generally are) used for most structure-based drug design (SBDDa) and indeed most molecular modeling, the importance of flexibility was recognized immediately: hemoglobin has two rather different structures,“tense” and “relaxed”, depending on its oxygenation, although in recent years a family of relaxed hemoglobin structures with different tertiary structure conformations have been reported. 6 In fact, all proteins are inherently flexible systems. This flexibility is frequently essential for function (eg, as in hemoglobin). Proteins have an intrinsic ability to undergo functionally relevant conformational transitions under native state conditions7, 8 on a wide range of scales, both in time and space. 9 In adenylate kinase large conformational changes due to movements of the nucleotide “lids”(ratelimiting for overall catalytic turnover10, 11) are “linked” with