Accessible Requires Authentication Published by De Gruyter June 7, 2019

Fragment-based drug design of nature-inspired compounds

Abdulkarim Najjar, Abdurrahman Olğaç, Fidele Ntie-Kang and Wolfgang Sippl
From the journal Physical Sciences Reviews

Abstract

Natural product (NP)-derived drugs can be extracts, biological macromolecules, or purified small molecule substances. Small molecule drugs can be originally purified from NPs, can represent semisynthetic molecules, natural fragments containing small molecules, or are fully synthetic molecules that mimic natural compounds. New semisynthetic NP-like drugs are entering the pharmaceutical market almost every year and reveal growing interests in the application of fragment-based approaches for NPs. Thus, several NP databases were constructed to be implemented in the fragment-based drug design (FBDD) workflows. FBDD has been established previously as an approach for hit identification and lead generation. Several biophysical and computational methods are used for fragment screening to identify potential hits. Once the fragments within the binding pocket of the protein are identified, they can be grown, linked, or merged to design more active compounds. This work discusses applications of NPs and NP scaffolds to FBDD. Moreover, it briefly reviews NP databases containing fragments and reports on case studies where the approach has been successfully applied for the design of antimalarial and anticancer drug candidates.

List of abbreviations

cLogP

The calculated logarithm of n-octanol/water partition coefficient

Da

Daltons

FBDD

Fragment-based drug design

HTS

High-throughput screening

LE

Ligand efficiency

LLE

Ligand lipophilicity efficiency

MW

Molecular weight

NP

Natural product

SM

Secondary metabolite

Acknowledgements

The work of AO was partially supported by the Scientific and Technological Research Council of Turkey (Technology and Innovation Funding Programmes Directorate Grant Number 7141231) and EU financial support, received through the cHiPSet COST Action IC1406. FNK acknowledges a Georg Forster return fellowship and equipment subsidy from the Alexander von Humboldt Foundation, Germany. Financial support is acknowledged from a ChemJets Fellowship awarded to FNK from the Ministry of Education, Youth and Sport, Czech Republic.

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Published Online: 2019-06-07

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