Ligand-receptor structures

These databases are a rich source of information, yet they do not capture an element of interest, namely the biological endpoint there is no searchable field to identify, in a quantitative manner, what is the target-related activity of a particular compound. Such information is important if one considers that (a) not all chemotypes indexed in patent databases are indeed active - some are just patent claims with no factual basis and that (b) not aU chemotypes disclosed as active are equally active, or selective for that matter, on the target of choice. Furthermore, should one decide to pursue a certain interaction hotspot in a given ligand-receptor structure (assuming good structure-activity models are available), it would be very convenient to mine structure-activity databases for similar chemotypes to use as potential bioisosteric replacements. 

Dynamic uneasiness prevailing in the ligand-receptor structures together with the conformational flexibility of the target and the drug is extremely vital and important. 

As an example for an efficient yet quite accurate approximation, in the first part of our contribution we describe a combination of a structure adapted multipole method with a multiple time step scheme (FAMUSAMM — fast multistep structure adapted multipole method) and evaluate its performance. In the second part we present, as a recent application of this method, an MD study of a ligand-receptor unbinding process enforced by single molecule atomic force microscopy. Through comparison of computed unbinding forces with experimental data we evaluate the quality of the simulations. The third part sketches, as a perspective, one way to drastically extend accessible time scales if one restricts oneself to the study of conformational transitions, which arc ubiquitous in proteins and are the elementary steps of many functional conformational motions. 

These structural key descriptors incorporate a remarkable amount of pertinent molecular arrangements covering each type of interaction involved in ligand-receptor bindings [26]. Since every structure in a database is represented by one or more of the 960 key codes available in ISIS, suppose that two molecules include respectively A and B key codes, then the Tanimoto coefficient is given by ... 

Nothacker HP, Reinscheid, RK, Civelli O (2001) From receptor to ligand. In Stanford C, Horton R (eds) Receptors Structure and function. CRC press, Oxford pp. 41-63... 

Arylpiperazines have immensely important effects on various and diverse biological targets, in particular on CNS receptors. In the case of serotonin (5-HT) receptors, compounds containing this arylpiperazine moiety represent the largest systematically studied class of 5-HTia receptor ligands [63]. Structural alterations within long-chain arylpiperazines (LCAPs) occur mainly at the two opposite ends of a molecule and have been described by many authors [64-71]. 

The crystal structures of monomeric ligands such as GH and EPO in complex with their respective receptors show that these hormones are bivalent and one ligand binds simultaneously to two receptor molecules to form a 1 2 (ligand receptor) complex. Receptor dimerization is further stabilized by additional receptor-receptor interactions. 

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