Incorporating QSPR in the enumeration of fragment space
Juri Pärn, Matthias Rarey · Chemistry Central Journal · 2009
The generation of novel bioactive compounds based onexisting lead series is a frequently occurring challenge indrug development programs. Bioactivity itself has differ-ent aspects which have to be taken into account. Whilerules based on simple descriptors like Lipinski's rule offive [1] for bioavailability exist, in most cases pharmaco-logically important properties have to be predicted via sta-tistical models since no direct calculation method isknown.For the lead search and optimization phase, the represen-tation of the search space is of crucial importance. Chem-ical fragment spaces are a relatively new and a promisingapproach to model the chemical space in a combinatorialway. A chemical fragment space consists of a set of molec-ular fragments and a set of rules [2][3]. Each fragment hasone or several link atoms, each having a certain type. Theset of rules primarily defines which link types are compat-ible to each other. New chemical entities are generated byconnecting fragments using the link atoms according tothe compatibility definition.Based on the idea of recombining fragments of bioactivecompounds, we developed a program to enumerate frag-ment spaces. Since a complete enumeration is in mostcases not possible and not desirable our program onlyenumerates certain parts of a fragment space. The user candefine which part of the space should be enumerated byproviding min-max ranges for physicochemical con-straints which the resulting molecules have to obey [4]. Totake properties into consideration which can not bedirectly derived from simple descriptors, we implementedand incorporated a PLS based QSPR prediction directlyinto our enumeration engine. The QSPR-model derivedproperties can either be written out with the molecules orthey can be used as filter in the enumeration. As descriptorfor the QSPR-model we use a reduced graph representa-tion of a molecule. We reduce the number of differentatoms to six pharmacophoric types and count the numberof pairs over topological distances.The integration of QSPR models into the enumerationmethodology allows to create molecules from fragmentspaces lying within user specified property and QSPR-model ranges. The method can be applied in the leadidentification process but might also be useful to studythe limitation of QSPR models by creating large, diversecompound sets falling into the same range of predictedQSPR values.