Lead optimization mapper: automating free energy calculations for lead optimization.
Alchemical free energy calculations hold increasing promise as an aid to drug discovery efforts. However, applications of these techniques in discovery projects have been relatively few, partly because of the difficulty of planning and setting up calculations. Here, we introduce lead optimization mapper, LOMAP, an automated algorithm to plan efficient relative free energy calculations between potential ligands within a substantial library of perhaps hundreds of compounds. In this approach, ligands are first grouped by structural similarity primarily based on the size of a (loosely defined) maximal common substructure, and then calculations are planned within and between sets of structurally related compounds. An emphasis is placed on ensuring that relative free energies can be obtained between any pair of compounds without combining the results of too many different relative free energy calculations (to avoid accumulation of error) and by providing some redundancy to allow for the possibility of error and consistency checking and provide some insight into when results can be expected to be unreliable. The algorithm is discussed in detail and a Python implementation, based on both Schrödinger's and OpenEye's APIs, has been made available freely under the BSD license.
Department of Pharmaceutical Sciences and Department of Chemistry, University of California, Irvine, 147 Bison Modular, Irvine, CA, 92697, USA.
Shuai
S
Liu
Yujie
Y
Wu
Teng
T
Lin
Robert
R
Abel
Jonathan P
JP
Redmann
Christopher M
CM
Summa
Vivian R
VR
Jaber
Nathan M
NM
Lim
David L
DL
Mobley
D000465:Algorithms; D001331:Automation; D001665:Binding Sites; D015195:Drug Design; D055808:Drug Discovery; D019277:Entropy; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D006801:Humans; D008024:Ligands; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D012984:Software; D013816:Thermodynamics; D014357:Trypsin / Q000737:chemistry / Q000378:metabolism
D004791:Enzyme Inhibitors; D065427:Factor Xa Inhibitors; D008024:Ligands; D014357:Trypsin; D015951:Factor Xa