Fragment‐Based Lead Discovery: Screening and Optimizing Fragments for Thermolysin Inhibition

Fragment‐based drug discovery has gained a foothold in today's lead identification processes. We present the application of in silico fragment‐based screening for the discovery of novel lead compounds for the metalloendoproteinase thermolysin. We have chosen thermolysin to validate our screening approach as it is a well‐studied enzyme and serves as a model system for other proteases. A protein‐targeted virtual library was designed and screening was carried out using the program AutoDock. Two fragment hits could be identified. For one of them, the crystal structure in complex with thermolysin is presented. This compound was selected for structure‐based optimization of binding affinity and improvement of ligand efficiency, while concomitantly keeping the fragment‐like properties of the initial hit. Redesigning the zinc coordination group revealed a novel class of fragments possessing K_i values as low as 128 μM , thus they provide a good starting point for further hit evolution in a tailored lead design.     

From On‐Target to Off‐Target Activity: Identification and Optimisation of Trypanosoma brucei GSK3 Inhibitors and Their Characterisation as Anti‐Trypanosoma brucei Drug Discovery Lead Molecules

Human African trypanosomiasis (HAT) is a life‐threatening disease with approximately 30 000–40 000 new cases each year. Trypanosoma brucei protein kinase GSK3 short (TbGSK3) is required for parasite growth and survival. Herein we report a screen of a focused kinase library against T. brucei GSK3. From this we identified a series of several highly ligand‐efficient TbGSK3 inhibitors. Following the hit validation process, we optimised a series of diaminothiazoles, identifying low‐nanomolar inhibitors of TbGSK3 that are potent in vitro inhibitors of T. brucei proliferation. We show that the TbGSK3 pharmacophore overlaps with that of one or more additional molecular targets.     

Anti-influenza Drug Discovery: Identification of an Orally Bioavailable Quinoline Derivative through Activity- and Property-Guided Lead Optimization

From a high-throughput screening (HTS) hit with inhibitory activity against virus-induced cytophathic in the low micromolar range, we have developed a potent anti-influenza lead through careful optimization without compromising the drug-like properties of the compound. An orally bioavailable compound was identified as a lead agent with nanomolar activity against influenza, representing a 140-fold improvement over the initial hit.     

Puckering the Planar Landscape of Fragments: Design and Synthesis of a 3D Cyclobutane Fragment Library

Fragment-based drug discovery (FBDD) has a growing need for unique screening libraries. The cyclobutane moiety was identified as an underrepresented yet attractive three-dimensional (3D) scaffold. Synthetic strategies were developed via a key 3-azido-cyclobutanone intermediate, giving potential access to a range of functional groups with accessible growth vectors. A focused set of 33 novel 3D cyclobutane fragments was synthesised, comprising three functionalities: secondary amines, amides, and sulfonamides. This library was designed using Principal Component Analysis (PCA) and an expanded version of the rule of three (RO3), followed by Principal Moment of Inertia (PMI) analysis to achieve both chemical diversity and high 3D character. Cis and trans ring isomers of library members were generated to maximise the shape diversity obtained, while limiting molecular complexity through avoiding enantiomers. Property analyses of the cyclobutane library indicated that it fares favourably against existing synthetic 3D fragment libraries in terms of shape and physicochemical properties.     

α‐Amylase Modulation: Discovery of Inhibitors Using a Multi‐Pharmacophore Approach for Virtual Screening

Better control of postprandial hyperglycemia can be achieved by delaying the absorption of glucose resulting from carbohydrate digestion. Because α‐amylase initiates the hydrolysis of polysaccharides, the design of α‐amylase inhibitors can lead to the development of new treatments for metabolic disorders such as type II diabetes and obesity. In this study, a rational computer‐aided approach was developed to identify novel α‐amylase inhibitors. Three‐dimensional pharmacophores were developed based on the binding mode analysis of six different families of compounds that bind to this enzyme. In a stepwise virtual screening workflow, seven molecules were selected from a library of 1.4 million. Five out of seven biologically tested compounds showed α‐amylase inhibition, and the two most potent compounds inhibited α‐amylase with IC₅₀ values of 17 and 27 μm . The scaffold benzylideneacetohydrazide was shared by four of the discovered inhibitors, emerging as a novel drug‐like non‐carbohydrate fragment and constituting a promising lead scaffold for α‐amylase inhibition.     

Sulfonated Reduced Graphene Oxide (RGO-SO3H): As an Efficient Nanocatalyst for One-Pot Synthesis of 2-Amino-3-cyano-7-hydroxy-4H-chromenes Derivatives in Water

Sulfonated reduced graphene oxide (RGO-SO₃H) was found to be an efficient catalyst for one-pot synthesis of a class of 2-amino-3-cyano-7-hydroxy-4H-chromenes derivatives using multicomponent reaction (MCR) of phenols, aldehydes and malononitrile under mild and green conditions. The reaction was performed in water as a green solvent and range of 2-amino-3-cyano-7-hydroxy-4H-chromenes were obtained in good to excellent yields. The RGO-SO₃H was reusable at least 5 times without significant decrease in its catalytic activity.     

Towards Dynamic Drug Design: Identification and Optimization of β‐Galactosidase Inhibitors from a Dynamic Hemithioacetal System

A discovery strategy relying on the identification of fragments through resolution of a constitutional dynamic system, coupled to subsequent static ligand design and optimization, is demonstrated. The strategic design and synthesis of the best molecular fragments identified from a dynamic hemithioacetal system into static ligand structures yielded a range of β‐galactosidase inhibitors. Two series of structures mimicking the hemithioacetal motif were envisaged: thioglycosides and C‐glycosides. Inhibition studies provided important structural information for the two groups, and 1‐thiobenzyl‐β‐D ‐galactopyranoside demonstrated the best inhibitory effects.     

A New Paradigm for KIM-PTP Drug Discovery: Identification of Allosteric Sites with Potential for Selective Inhibition Using Virtual Screening and LEI Analysis

The kinase interaction motif protein tyrosine phosphatases (KIM-PTPs), HePTP, PTPSL and STEP, are involved in the negative regulation of mitogen-activated protein kinase (MAPK) signalling pathways and are important therapeutic targets for a number of diseases. We have used VSpipe, a virtual screening pipeline, to identify a ligand cluster distribution that is unique to this subfamily of PTPs. Several clusters map onto KIM-PTP specific sequence motifs in contrast to the cluster distribution obtained for PTP1B, a classic PTP that mapped to general PTP motifs. Importantly, the ligand clusters coincide with previously reported functional and substrate binding sites in KIM-PTPs. Assessment of the KIM-PTP specific clusters, using ligand efficiency index (LEI) plots generated by the VSpipe, ascertained that the binders in these clusters reside in a more drug-like chemical–biological space than those at the active site. LEI analysis showed differences between clusters across all KIM-PTPs, highlighting a distinct and specific profile for each phosphatase. The most druggable cluster sites are unexplored allosteric functional sites unique to each target. Exploiting these sites may facilitate the delivery of inhibitors with improved drug-like properties, with selectivity amongst the KIM-PTPs and over other classical PTPs.     

Controlled Reversible Anchoring of η6‐Arene/TsDPEN‐ Ruthenium(II) Complex onto Magnetic Nanoparticles: A New Strategy for Catalyst Separation and Recycling

A new catalyst separation and recycling protocol combining magnetic nanoparticles and host‐guest assembly was developed. The catalyst, (η⁶‐arene)[N‐(para‐toluenesulfonyl)‐1,2‐diphenylethylenediamine]ruthenium trifluoromethanesulfonate [Ru(OTf)(TsDPEN)(η⁶‐arene)] bearing a dialkylammonium salt tag, was easily separated from the reaction mixtures by magnet‐assisted decantation, on basis of the formation of a pseudorotaxane complex by using dibenzo[24]crown‐8‐modified Fe₃O₄ nanoparticles. The ruthenium catalyst has been successfully reused at least 5 times with the retention of enantioselectivity but at the expense of relatively low catalytic activities in the asymmetric hydrogenation of 2‐methylquinoline.