CASE STUDY IDENTIFICATION OF PRIVILEGED FRAGMENTS USING IN SILICO MOLECULES FRAGMENTATION METHODS: THE CASE FOR CNS PENETRANT MOLECULES

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1 : Executive Summary T he identification of novel reagents, the building blocks for the synthesis of potential Central Nervous System (CNS) drugs through array/combinatorial chemistry, is of great interest to pharmaceutical companies involved in this therapeutic area. In the study cited herein, in silico molecular fragmentation methods were used since they have demonstrated their efficiency in extracting useful information. Research has shown that the identification of privileged fragments occur more frequently within ligands of particular targets or target classes with respect to inactive compounds. Existing collections of CNS and non-cns drugs were fragmented in order to identify, by comparison, privileged core structures in terms of physicochemical properties. Such privileged fragments were then translated into appropriate reagents to be used for synthesizing focused arrays of molecules. A scientific team with expertise in Medicinal Chemistry, Rational Drug Design and Integrated lead optimization collaborated to develop these findings. 1

2 The Challenge In order to become available for binding to a specific target, CNS active molecules need to cross the Blood Brain Barrier usually through passive diffusion, unless actively transported. This factor, in conjunction with many other parameters such as plasma and tissue binding that determine drug efficiency, confer defined ranges of physiochemical properties to these molecules. Marketed CNS drugs usually have relatively low Molecular Weight (MW), a compact and rigid structure, only a few hydrogen bond donors/acceptors and a reduced polar surface area. The main challenge was to include these physicochem CNS requirements into the selection and design of appropriate scaffold and reagents amenable for the synthesis of CNS biased arrays/libraries. The Solution Two fragmentation methods were used: one based on a retro-synthesis approach; the other, developed in-house, based on a pure topological perception of rings and linkers, R&L (Figure 1). Reaction schemes used for sets fragmentations. RECAP reactions extended with 18 more definitions Ad-hoc newly added reactions Non chemically aware fragmentation scheme Figure 1 2

3 After fragmentation of the CNS and non-cns drugs datasets (Figure 2), simple physicochemical properties were computed and compared, focusing on fragments with two or three attachment points since these represented the majority of the so called core structures. 1. World Drug Index (WDI) From the World Drug Index database after removal of FUNGICICE, HERBICIDE, STEROIDS, β-lactams, POLIPEPTIDES and METALS and MW<1000 ( 2. Pharmstructure Derived from the Pharmaproject database ( 3. Marketed Drugs From a list of ~2500 reference drugs currently on the market 4. Drugs (no CNS Drugs) From the World Drug Index database with an US approved Name (USAN) and Pharmaproject with the Licensed flag. A Molecular Weight cut-off of 100 MW 800 was also used 5. CNS Drugs From the World Drug Index database but only for drugs with indications for CNS targets. FDA approved drugs for Neurology and Psychiatry/Psychology during ( druglist.htm) were also added if structure fond on the WDI and not already included in database 56k 15k 2.5k 5.8k 525 Figure 2 All fragmentations schemes were encoded as SMIRKS definitions (example: amide retrosynthetic formation) (Figure 3) Figure 3 3

4 Comparison of whole molecule properties such as MW, Hydrogen Bond Donors/Acceptors (HBD/HBA) and topological Polar Surface Area (TPSA) was conducted to estimate the suitable chemical space for scaffold decoration. This analysis resulted in the identification of the following generic cut-off criteria for a CNS core: MW ; HBA 0-2; HBD 0-1; TPSA 0-50; NEG 0; POS 0-1. The application of these filters to a number of fragmented databases cited in Figure 2, followed by the estimation of the relative frequency of the cores in the supplemental internal and literature databases (accessed through SciFinder), led to a process resulting in the identification of novel CNS scaffolds. Comparison of Physchem properties of CNS cores vs CNS full molecules Figure 4 4

5 In this example, the focus is on small spiro cores. Frequency of spiro cores was computed on a corporate database as well as databases 1, 2 and 3 as shown in Figure 2 (Page 3). This calculation was done for both the RECAP and R&L fragmentation protocol. Among all the possible spiro cores, one (SPIRO C) was selected for potential interest because it was present in only a few molecules within the corporate collection (256). It was novel in terms of known drugs and it was not very frequent within published literature (only 12 structures reported on patents, and 18 on papers). The workflow used to identify potential spiro CNS core structures is shown. Within the context of identifying cores suitable for the creation of CNS arrays/libraries based on physicochemical cut-offs, the research is important to pharmaceutical companies that are especially interested in those cores that were not overly represented within the internal screening collection (internal novelty) and/or overly exemplified in the patent literature (external novelty). Again, the fragmentation approach provided valuable insights on how to access pertinent information in a very effective manner. Figure 5 5

6 Conclusion As shown, a workflow protocol aimed at identifying valuable core structures for the synthesis of chemical libraries for CNS targets was developed using molecule fragmentation. While the physicochemical properties of the entire molecule are the main driving factor, applying such cut-offs at a smaller moiety level can increase the scope for future synthetic efforts aimed to optimize/grow such molecules. A pragmatic benefit of such a method is that it can be used to screen commercially available reagents, therefore providing a valuable and abundant source of rapidly available starting points. Aptuit people join their heads for science and their hearts for service to realize customer goals as efficiently, expeditiously and economically as possible, always at the highest level of quality. References are available upon request. For information about Aptuit s services, please contact us: in Europe: in the US: us at: info@aptuit.com 6