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. 2023 Jun;27(3):1459-1468.
doi: 10.1007/s11030-022-10506-5. Epub 2022 Aug 4.

Towards systematic exploration of chemical space: building the fragment library module in molecular property diagnostic suite

Anamika Singh Gaur  1   2   3 , Lijo John  1   2   3 , Nandan Kumar  1 , M Ram Vivek  2 , Selvaraman Nagamani  1   3 , Hridoy Jyoti Mahanta  1   3 , G Narahari Sastry  4   5
Affiliations

Towards systematic exploration of chemical space: building the fragment library module in molecular property diagnostic suite

Anamika Singh Gaur et al. Mol Divers. 2023 Jun.

Abstract

A fragment-based drug discovery (FBDD) approach has traditionally been of utmost significance in drug design studies. It allows the exploration of large chemical space to find novel scaffolds and chemotypes which can be improved into selective inhibitors with good affinity. In the current work, several public domain chemical libraries (ChEMBL, DrugCentral, PDB ligands, COCONUT, and SAVI) comprising bioactive and virtual molecules were retrieved to develop a fragment library. A systematic fragmentation method that breaks a given molecule into rings, linkers, and substituents was used to cleave the molecules and the fragments were analyzed. Further, only the ring framework was taken into the consideration to develop a fragment library that consists of a total number of 107,614 unique fragments. This set represents a rich diverse structure framework that covers a wide variety of yet-to-be-explored fragments for a wide range of small molecule-based applications. This fragment library is an integral part of the molecular property diagnostic suite (MPDS) suite that can be used with other modeling and informatics methods for FBDD approaches. The fragment library module of MPDS can be accessed at http://mpds.neist.res.in:8085 .

Keywords: Drug discovery; Fragment library; Fragment space; MPDS.

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Conflict of interest statement

The authors have no conflict of interest.

Figures

Scheme 1
Scheme 1
The integrative methodology used for the generation of the fragment library
Fig. 1
Fig. 1
Process of generation of fragments from molecules into rings, linkers, and substituents
Fig. 2
Fig. 2
The percentage of common fragments based on its structural diversity
Fig. 3
Fig. 3
Percentage distribution of the ring fragments in the dataset based on A type of ring and B different databases
Fig. 4
Fig. 4
Ten most frequent unique fragments from monocyclic, bicyclic, tricyclic, tetracyclic, and polycyclic groups against the ChEMBL database. The occurrence of these fragments in the ChEMBL dataset is indicated in the normal font and the percentage in bold font
Fig. 5
Fig. 5
Distribution of unique fragments based on heteroatoms
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