caa a22 4500 46793889X CHVBK 20180406153006.0 cr unu---uuuuu 170328e20060401xx s 000 0 eng 10.1007/s10822-006-9045-3 doi (NATIONALLICENCE)springer-10.1007/s10822-006-9045-3 Electrostatic evaluation of isosteric analogues [Elektronische Daten] [Roger Sayle, Anthony Nicholls] A method is presented for enumerating a large number of isosteric analogues of a ligand from a known protein-ligand complex structure and then rapidly calculating an estimate of their binding energies. This approach takes full advantage of the observed crystal structure, by reusing the atomic co-ordinates determined experimentally for one ligand, to approximate those of similar compounds that have approximately the same shape. By assuming that compounds with similar shapes adopt similar binding poses, and that entropic and protein flexibility effects are approximately constant across such an isosteric series ("the frozen ligand approximation”), it is possible to order their binding affinities relatively accurately. Additionally, the constraint that the atomic coordinates are invariant allows for a dramatic simplification in the Poisson-Boltzmann method used to calculation the electrostatic component of the binding energy. This algorithmic improvement allows for the calculation of tens of thousands of binding energies per second for drug-like molecules, enabling this technique to be used in screening large virtual libraries of isosteric analogues. Most significantly, this procedure is shown to be able to reproduce SAR effects of subtle medicinal chemistry substitutions. Finally, this paper reports the results of the proposed methodology on␣seven model systems; dihydrofolate reductase, Lck␣kinase, ribosome inactivating protein, l-arabinose binding protein, neuraminidase, HIV-1 reverse transcriptase and COX-2. Springer Science+Business Media B.V., 2006 WABE nationallicence Docking nationallicence Isosteres nationallicence Electrostatics nationallicence Frozen ligand approximation nationallicence De novo structure based drug design nationallicence Poisson-Boltzmann equation nationallicence Sayle Roger OpenEye Scientific Software, Suite 1107, 3600 Cerrillos Road, 87507, Santa Fe, New Mexico, USA aut Nicholls Anthony OpenEye Scientific Software, Suite 1107, 3600 Cerrillos Road, 87507, Santa Fe, New Mexico, USA aut Journal of Computer-Aided Molecular Design Kluwer Academic Publishers 20/4(2006-04-01), 191-208 0920-654X 20:4<191 2006 20 10822 https://doi.org/10.1007/s10822-006-9045-3 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10822-006-9045-3 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Sayle Roger OpenEye Scientific Software, Suite 1107, 3600 Cerrillos Road, 87507, Santa Fe, New Mexico, USA aut NATIONALLICENCE 700 1- Nicholls Anthony OpenEye Scientific Software, Suite 1107, 3600 Cerrillos Road, 87507, Santa Fe, New Mexico, USA aut NATIONALLICENCE 773 0- Journal of Computer-Aided Molecular Design Kluwer Academic Publishers 20/4(2006-04-01), 191-208 0920-654X 20:4<191 2006 20 10822 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer