Fragment-based drug design of nature-inspired compounds

Abstract

<jats:title>Abstract</jats:title> <jats:p>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.</jats:p>

Fragment tailoring strategy to design novel chemical entities as potential binders of novel corona virus main protease

“…Fragment structures were downloaded in the form of .sdf files from 4 different publicly available libraries, viz., Asinex fragments and building blocks (http://www.asinex.com/fragments/), FCH group's (http://fchgroup.net/fragment-libraries.php) 'all purpose' fragment library, fluorine fragment library, fragment like acids, fragment like amines, fragment like amino acids, high fsp 3 fragment library, spiro fragments and FCH special selection of fragment library and ChemDiv (https://www.chemdiv.com/) fragment library. A consolidated set of 191678 unique fragments were verified for the 'rule of 3 0 (Najjar et al, 2019) agreement and considered for fragment-based design. All the fragments were subjected to preparation in LigPrep (LigPrep, Schr€ odinger, LLC, New York, NY, 2019), generating their ionization states at pH 7.0 (± 2.0) using Epik ionizer.…”

Fragment tailoring strategy to design novel chemical entities as potential binders of novel corona virus main protease

“…Fragment libraries: Fragment structures were downloaded in the form of .sdf files from 4 different publicly available libraries, viz., Asinex fragments and building blocks [39], FCH group's [40] 'all purpose' fragment library, fluorine fragment library, fragment like acids, fragment like amines, fragment like amino acids, high fsp 3 fragment library, spiro fragments and FCH special selection of fragment library and ChemDiv [41] fragment library and. A consolidated set of 191678 unique fragments were verified for the 'rule of 3' [42] agreement and considered for fragment-based design. All the fragments were subjected to preparation in LigPrep [43], generating their ionization states at pH 7.0 (± 2.0) using Epik ionizer.…”

TWN-FS method: A novel fragment screening method for drug discovery

“…The FBDD strategy involves identifying fragments that interact with the binding hot spot [6] , which refers to the specific region in the binding site contributing the most to the protein-ligand binding free energy. Subsequently, these fragments are linked, grown and merged to design potential drug candidates [7] , [8] . Kinases are important targets for the drug development and FBDD is particularly suitable for the development of novel kinase inhibitors because the binding pockets of kinases are well-characterized.…”