Scaffold Hopping Research Articles

Deconstructive Functionalization of Ketones via an LMCT-Promoted C–C Cleavage

In this issue of Chem, Zuo and coworkers report an exciting new strategy for the deconstructive functionalization of ketones. Through merging Lewis-acid-catalyzed nucleophilic 1,2-addition and ligand-to-metal charge transfer (LMCT)-promoted C–C cleavage, common strained and unstrained ketones are transformed into synthetically valuable scaffolds with high efficiency under mild conditions.

Scaffold hopping enables direct access to more potent PROTACs with in vivo activity.

Herein we employ a scaffold hopping approach to enhance the activity of a previously reported BCR-Abl PROTAC. This represents a significant advance in the PROTAC field since it can abrogate the need to optimize the linker to access a more potent degrader. The new PROTAC demonstrates a >10 fold increase in ability to induce degradation and demonstrates in vivo activity.

Scaffold Hopping of Natural Product Evodiamine: Discovery of a Novel Antitumor Scaffold with Excellent Potency against Colon Cancer.

Inspired by the natural product evodiamine, a novel antitumor indolopyrazinoquinazolinone scaffold was designed by scaffold hopping. Structure-activity relationship studies led to the discovery of compound 15j, which shows low nanomolar inhibitory activity against the HCT116 cell line. Further antitumor mechanism studies indicated that compound 15j acted by the dual inhibition of topoisomerase 1 and tubulin and induced apoptosis with G2 cell-cycle arrest. The quaternary ammonium salt of compound 15j (compound 15js) exhibited excellent in vivo antitumor activity (TGI = 66.6%) in the HCT116 xenograft model with low toxicity. Indolopyrazinoquinazolinone derivatives represent promising multitargeting antitumor leads for the development of novel antitumor agents.

Discovery of novel N-sulfonamide-tetrahydroquinolines as potent retinoic acid receptor-related orphan receptor γt inverse agonists for the treatment of autoimmune diseases

Targeting the nuclear receptor RORγt is thought to be effective in autoimmune disorders. Tertiary sulfonamide 1 was found to be a potent RORγt inverse agonist previously. However, the high hepatic clearance value limits its druggability. In this study, we designed and synthesized a series of N-sulfonamide-tetrahydroquinolines by molecular modeling and scaffold hopping strategy, aiming at improving the metabolic stabilities. Detailed SAR exploration led to identification of potent RORγt inverse agonists such as 13 with moderate binding affinity and inhibitory activity of Th17 cell differentiation. Binding mode of 13 with RORγt-LBD was revealed by molecular docking. Moreover, 13 showed lower intrinsic clearance in mouse liver microsomes compared with 1 and potent in vivo efficacy and safety in psoriasis models, which can be used as a good starting point for the further optimization.

Covalent Inhibition of the Histamine H3 Receptor.

Covalent binding of G protein-coupled receptors by small molecules is a useful approach for better understanding of the structure and function of these proteins. We designed, synthesized and characterized a series of 6 potential covalent ligands for the histamine H3 receptor (H3R). Starting from a 2-amino-pyrimidine scaffold, optimization of anchor moiety and warhead followed by fine-tuning of the required reactivity via scaffold hopping resulted in the isothiocyanate H3R ligand 44. It shows high reactivity toward glutathione combined with appropriate stability in water and reacts selectively with the cysteine sidechain in a model nonapeptide equipped with nucleophilic residues. The covalent interaction of 44 with H3R was validated with washout experiments and leads to inverse agonism on H3R. Irreversible binder 44 (VUF15662) may serve as a useful tool compound to stabilize the inactive H3R conformation and to study the consequences of prolonged inhibition of the H3R.

Discovery of Novel Inhibitors of LpxC Displaying Potent in Vitro Activity against Gram-Negative Bacteria.

UDP-3-O-((R)-3-hydroxymyristoyl)-N-glucosamine deacetylase (LpxC) is as an attractive target for the discovery and development of novel antibacterial drugs to address the critical medical need created by multidrug resistant Gram-negative bacteria. By using a scaffold hopping approach on a known family of methylsulfone hydroxamate LpxC inhibitors, several hit series eliciting potent antibacterial activities against Enterobacteriaceae and Pseudomonas aeruginosa were identified. Subsequent hit-to-lead optimization, using cocrystal structures of inhibitors bound to Pseudomonas aeruginosa LpxC as guides, resulted in the discovery of multiple chemical series based on (i) isoindolin-1-ones, (ii) 4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-ones, and (iii) 1,2-dihydro-3H-pyrrolo[1,2-c]imidazole-3-ones. Synthetic methods, antibacterial activities and relative binding affinities, as well as physicochemical properties that allowed compound prioritization are presented. Finally, in vivo properties of lead molecules which belong to the most promising pyrrolo-imidazolone series, such as 18d, are discussed.

In Silico Laboratory: Tools for Similarity-Based Drug Discovery.

Computational methods that predict and evaluate binding of ligands to receptors implicated in different pathologies have become crucial in modern drug design and discovery. Here, we describe protocols for using the recently developed package of computational tools for similarity-based drug discovery. The ProBiS stand-alone program and web server allow superimposition of protein structures against large protein databases and predict ligands based on detected binding site similarities. GenProBiS allows mapping of human somatic missense mutations related to cancer and non-synonymous single nucleotide polymorphisms and subsequent visual exploration of specific interactions in connection to these mutations. We describe protocols for using LiSiCA, a fast ligand-based virtual screening software that enables easy screening of large databases containing billions of small molecules. Finally, we show the use of BoBER, a web interface that enables user-friendly access to a large database of bioisosteric and scaffold hopping replacements.

Design, synthesis and biological evaluation of 2-arylaminopyrimidine derivatives bearing 1,3,8-triazaspiro[4,5]decan-4-one or piperidine-3-carboxamide moiety as novel Type-I1/2 ALK inhibitors.

Aiming to develop novel Type-I1/2 inhibitors of ALK to overcome extensive resistance mutations, especially the L1196M mutation surrounding the ATP pocket, two series of 2-arylaminopyrimidine derivatives (11a-f and 22a-t) were designed based on scaffold hopping. The extensive structural elaboration discovered compound 22o which possessed excellent IC50 values of 0.06 and 0.23μM against ALK-positive Karpas299 and H2228 cell lines, respectively. Meanwhile, 22o displayed encouraging inhibitory potency in the ALKWT (2.5nM) and ALKL1196M (6.5nM) enzymatic assays. Furthermore, the AO/EB and Hoechst 33258 assays illustrated 22o could induce cell apoptosis in a dose-dependent manner. Eventually, the molecular docking of 22o with ALK clearly presented the vital interactions within the active site, which was in accordance with Type-I1/2 inhibitor binding mode.

Perspective: present pesticide discovery paradigms promote the evolution of resistance - learn from nature and prioritize multi-target site inhibitor design.

For many years, the emphasis of industry discovery programs has been on finding new target sites of pesticides and finding pesticides that inhibit single targets. There had been an emphasis on genomics in finding single targets for potential pesticides. There is also the claim that registration of single target inhibiting pesticides is simpler if the mode of action is known. Conversely, if one looks at the evolution of resistance from an epidemiological perspective to ascertain which pesticides have been the most recalcitrant to evolutionary forces, it is those that have multiple target sites of action. Non-target-site resistances can evolve to multi-target-site inhibitors, but these resistances can often be overcome by structural modification of the pesticide. Industry has looked at pest-toxic natural products as pesticide leads, but seems to have abandoned those where they can find no single target of action. Perhaps nature has been intelligent and evolved many natural products that are synergistic multi-target-site inhibitors, and that is why natural compounds have been active for millennia? We should be learning from nature while combining new chemistry technologies with vast accrued databases and computer aided design allowing fragment-based discovery and scaffold hopping to produce multi-target site inhibitors instead of single target pesticides. © 2019 Society of Chemical Industry.

Applications of Deep-Learning in Exploiting Large-Scale and Heterogeneous Compound Data in Industrial Pharmaceutical Research.

In recent years, the development of high-throughput screening (HTS) technologies and their establishment in an industrialized environment have given scientists the possibility to test millions of molecules and profile them against a multitude of biological targets in a short period of time, generating data in a much faster pace and with a higher quality than before. Besides the structure activity data from traditional bioassays, more complex assays such as transcriptomics profiling or imaging have also been established as routine profiling experiments thanks to the advancement of Next Generation Sequencing or automated microscopy technologies. In industrial pharmaceutical research, these technologies are typically established in conjunction with automated platforms in order to enable efficient handling of screening collections of thousands to millions of compounds. To exploit the ever-growing amount of data that are generated by these approaches, computational techniques are constantly evolving. In this regard, artificial intelligence technologies such as deep learning and machine learning methods play a key role in cheminformatics and bio-image analytics fields to address activity prediction, scaffold hopping, de novo molecule design, reaction/retrosynthesis predictions, or high content screening analysis. Herein we summarize the current state of analyzing large-scale compound data in industrial pharmaceutical research and describe the impact it has had on the drug discovery process over the last two decades, with a specific focus on deep-learning technologies.

Discovery of a novel 3,4-dimethylcinnoline carboxamide M4 positive allosteric modulator (PAM) chemotype via scaffold hopping.

This Letter details our efforts to replace the 2,4-dimethylquinoline carboxamide core of our previous M4 PAM series, which suffered from high predicted hepatic clearance and protein binding. A scaffold hopping exercise identified a novel 3,4-dimethylcinnoline carboxamide core that provided good M4 PAM activity and improved clearance and protein binding profiles.

Synthesis and Neuroprotective Biological Evaluation of Quinazolinone Derivatives via Scaffold Hopping

To develop efficient method for the synthesis of quinazolinone derivatives bearing different functional groups on ring A and ring B and evaluation as neuroprotective agents. Synthetic route to quinazolinone derivatives was furnished by condensation/cyclocondensation/ reduction sequence of the activated N-acylbenzotriazoles. The structures of the targets compounds have been deduced upon their spectral data (1HNMR, 13CNMR and Mass spectroscopy). The neuroprotective activities of the synthesized compounds are also evaluated. Preliminary screening on a MPP+ induced SH-SY5Y cell injury model of the synthesized compounds resulted in four compounds (6q, 6r, 6u, and 8e) showed promising neural cell protection activities. The action mechanisms of these compounds on neuroprotection were then analyzed by docking and reverse docking modeling. A series of quinazolinone derivatives, including different substitution types on rings A and B were designed and synthesized via scaffold hopping. With the help of neuroprotective biological evaluation, several efficient therapeutic neuroprotective agents were found for further evaluation as drug candidate against neurodegenerative disorder.

Novel urate transporter 1 (URAT1) inhibitors: a review of recent patent literature (2016–2019)

ABSTRACTIntroduction: Human urate transporter 1 (URAT1), which is an influx transporter protein, is located at the apical surface of renal tubular cells and presumed to be the major transporter responsible for the reabsorption of urate from blood. About 90% of patients develop hyperuricemia due to insufficient urate excretion; thus, it is important to develop URAT1 inhibitors that could enhance renal urate excretion by blocking the reabsorption of urate anion.Areas covered: In this review, the authors addressed the patent applications (2016–2019) about URAT1 inhibitors and some medicinal chemistry strategies employed in these patents.Expert opinion: Substituent decorating, bioisosterism, and scaffold hopping are three common medicinal chemistry strategies used in the discovery of URAT1 inhibitors. Meanwhile, the introduction of sulfonyl group into small molecules has become one of the important strategies for structural optimization of URAT1 inhibitors. Furthermore, developing drug candidates targeting both URAT1 and xanthine oxidase (XOD) has attracted lots of interest and attention.

Lead Optimization Studies Towards Finding NS2B/NS3 Protease Targetspecific Inhibitors as Potential Anti-dengue Drug-like Compounds.

Dengue Fever is a major threatening global health issue caused by a mosquito-borne pathogen. Even though some anti-viral drugs are now available to reduce the disease severity. Still, there is a need of better drug compound to combat with dengue fever. The NS2B/NS3 protease is a major therapeutic drug target for Insilco drug discovery. Previously, we have performed a pharmacophore features based virtual screening studies, which has led to the identification of ZINC92615064 compound as a potent NS2B/NS3 protease inhibitor and demonstrated its potential to act as anti-dengue drug-like compound using computational approaches. In this present study, the identified lead compound ZINC92615064 has been made to undergo scaffold hopping based novel library generation, and the resulted novel library of compounds has been virtually screened on to NS2B/NS3 protease towards identifying novel proprietary scaffold of compound which is acting as a potent inhibitor for the given drug target of NS2B/NS3. A total of 16,847 novel designed compounds library was generated using the scaffold hopping technology based on the structure of the lead compound ZINC92615064. Out of which, compound design no. 3718 has shown the best binding potential with a predicted IC50 value of 417.13 nM along with a permissible range of ADMET properties based on its descriptor values. This NS2B/NS3 protease in complex with compound 3718 was subjected to a rigorous molecular dynamic simulation study to further validate this complex thermodynamic stability, along with the aim to reveal the underlying molecular level interactions and potential mode of action.

1962P - Discovery of clinical candidate DBPR112, a furanopyrimidine-based epidermal growth factor receptor inhibitor for the treatment of non-small cell lung cancer

BackgroundLung cancer has the highest rate of morbidity and mortality among various cancer types, being responsible for over 1.69 million deaths per year. Approximately 80–85% of the lung cancer patients diagnosed present non-small cell lung cancer (NSCLC), while 10–15% present small cell lung cancer (SCLC). Mutations in the epidermal growth factor receptor (EGFR) have been observed in ∼50% of patients, in particular, in East Asian NSCLC patients. The single-point mutation L858R (exon 21) and amino acids deletions in the tyrosine kinase (TK) domain (exon 19) constitute 90% of all EGFR-activating mutations. MethodsWe introduced an acrylamide group as a Michael acceptor, resulting in compound 2, which showed potent in vitroactivity in both wild and mutant EGFR kinases and potent anti-proliferative activity in HCC827 lung cancer cell line. In this work, we apply SBDD to guide the optimization of lead compound 2and perform a detailed structure-activity relationship (SAR) study to bring this drug candidate into the next development stage. ResultsWe optimized the compound 2by scaffold hopping and by exploiting the potent inhibitory activity of various warhead groups. The results of the multi-objective optimization obtained the clinical candidate, compound 78 (DBPR112), which not only displayed a potent inhibitory activity against EGFR L858R/T790M double mutations, but also exhibited 10-fold potency better than 3rd generation inhibitor, osimertinib, against three EGFR and one HER2 exon 20 insertion mutations, since there are currently no EGFR-directed therapies approved specifically for the treatment of this mutation. ConclusionsX-ray co-crystal study of EGFRWTKinase and compound 78 revealed the potential of future design for mutant-selective inhibitors. Finally, furanopyrimidine 78 was selected as a clinical candidate to conduct all preclinical experiments and is currently undergoing phase 1 clinical trial in Taiwan. Clinical trial identificationNCT03246854. Legal entity responsible for the studyThe authors. FundingNational Health Research Institutes, Taiwan. DisclosureAll authors have declared no conflicts of interest.

Discovery of a Furanopyrimidine-Based Epidermal Growth Factor Receptor Inhibitor (DBPR112) as a Clinical Candidate for the Treatment of Non-Small Cell Lung Cancer.

Epidermal growth factor receptor (EGFR)-targeted therapy in non-small cell lung cancer represents a breakthrough in the field of precision medicine. Previously, we have identified a lead compound, furanopyrimidine 2, which contains a (S)-2-phenylglycinol structure as a key fragment to inhibit EGFR. However, compound 2 showed high clearance and poor oral bioavailability in its pharmacokinetics studies. In this work, we optimized compound 2 by scaffold hopping and exploiting the potent inhibitory activity of various warhead groups to obtain a clinical candidate, 78 (DBPR112), which not only displayed a potent inhibitory activity against EGFRL858R/T790M double mutations but also exhibited tenfold potency better than the third-generation inhibitor, osimertinib, against EGFR and HER2 exon 20 insertion mutations. Overall, pharmacokinetic improvement through lead-to-candidate optimization yielded fourfold oral AUC better that afatinib along with F = 41.5%, an encouraging safety profile, and significant antitumor efficacy in in vivo xenograft models. DBPR112 is currently undergoing phase 1 clinical trial in Taiwan.

Design, Synthesis, Insecticidal Evaluation and Modeling Studies on 1,4,6,7- tetrahydropyrazolo[3,4-d][1,3]oxazine Derivatives: An Application of Scaffold Hopping Strategy on Fipronil

Background::As the first phenylpyrazole pesticide, fipronil has been widely used in crop protection and public hygiene. In the low energy conformation of fipronil, a pseudo-six-membered ring is observed through an intramolecular hydrogen bond.Methods: :A scaffold hopping strategy was applied to mimic the pseudo-six-membered ring of fipronil by non-aromatic ring. All compounds were synthesized with a proper synthetic route and characterized by 1H NMR, 13C NMR and high-resolution mass spectra. Insecticidal activities of all target compounds against Plutella xylostella were assessed by a professional organization. Physicochemical property prediction and docking study of these compounds with GABA receptor were also performed.Results::A series of 1,4,6,7-tetrahydropyrazolo[3,4-d][1,3]oxazine derivatives containing twenty-five compounds were designed, synthesized and evaluated. Several compounds exhibited moderate activities against Plutella xylostella. The strong electron-withdrawing groups are conducive to improve activities of this series of compounds against Plutella xylostella. Docking study showed that the most active compound 10 with nitro group could bind within the TM2 domain of GABA receptor, in which a hydrogen bond was observed with residue 6’Thr. The activity of 10 was weaker than fipronil due to the differences in physicochemical properties.Conclusion: :More attention should be paid to physicochemical properties during novel pesticide hit or lead design through scaffold hopping.

Forging New Scaffolds from Old: Combining Scaffold Hopping and Hierarchical Virtual Screening for Identifying Novel Bcl-2 Inhibitors.

Though virtual screening methods have proven to be potent in various instances, the technique is practically incomplete to quench the need of drug discovery process. Thus, the quest for novel designing approaches and chemotypes for improved efficacy of lead compounds has been intensified and logistic approaches such as scaffold hopping and hierarchical virtual screening methods were evolved. Till now, in all the previous attempts these two approaches were applied separately. In the current work, we made a novel attempt in terms of blending scaffold hopping and hierarchical virtual screening. The prime objective is to assess the hybrid method for its efficacy in identifying active lead molecules for emerging PPI target Bcl-2 (B-cell Lymphoma 2). We designed novel scaffolds from the reported cores and screened a set of 8270 compounds using both scaffold hopping and hierarchical virtual screening for Bcl-2 protein. Also, we enumerated the libraries using clustering, PAINS filtering, physicochemical characterization and SAR matching. We generated a focused library of compounds towards Bcl-2 interface, screened the 8270 compounds and identified top hits for seven families upon fine filtering with PAINS algorithm, features, SAR mapping, synthetic accessibility and similarity search. Our approach retrieved a set of 50 lead compounds. Finding rational approach meeting the needs of drug discovery process for PPI targets is the need of the hour which can be fulfilled by an extended scaffold hopping approach resulting in focused PPI targeting by providing novel leads with better potency.

Design, synthesis, and molecular docking studies of novel pyrazolyl 2-aminopyrimidine derivatives as HSP90 inhibitors.

A series of novel pyrazolyl 2-aminopyrimidine derivatives (7a-t) were designed based on scaffold hopping techniques, synthesized and biologically evaluated for their HSP90 inhibition and anticancer activity. Several compounds exhibited potent HSP90 inhibition with IC50 values less than that of the reference standard 17-AAG (1.25 µM). The most potent compound 7t displayed excellent HSP90 inhibition with an IC50 of 20 nM and in vitro antiproliferative potential against three cancer cell lines (IC50 < 5 µM). 7t also induced dose dependent degradation of client proteins (pHER2 and pERK1/2) in Western blot analysis. Several structural features of 7p-t oriented the molecules to retain all the essential binding interactions with HSP90, as observed by rationalized docking studies. Therefore, the para-nitrophenyl ring on the central pyrazole ring along with the 2-amino group on the pyrimidine ring are the crucial features in the development of novel HSP90 inhibitors based on this scaffold for targeted anticancer therapy.

Combining structural and bioactivity-based fingerprints improves prediction performance and scaffold\xa0hopping capability

This study aims at improving upon existing activity predictions methods by augmenting chemical structure fingerprints with bio-activity based fingerprints derived from high-throughput screening (HTS) data (HTSFPs) and thereby showcasing the benefits of combining different descriptor types. This type of descriptor would be applied in an iterative screening scenario for more targeted compound set selection. The HTSFPs were generated from HTS data obtained from PubChem and combined with an ECFP4 structural fingerprint. The bioactivity-structure hybrid (BaSH) fingerprint was benchmarked against the individual ECFP4 and HTSFP fingerprints. Their performance was evaluated via retrospective analysis of a subset of the PubChem HTS data. Results showed that the BaSH fingerprint has improved predictive performance as well as scaffold hopping capability. The BaSH fingerprint identified unique compounds compared to both the ECFP4 and the HTSFP fingerprint indicating synergistic effects between the two fingerprints. A feature importance analysis showed that a small subset of the HTSFP features contribute most to the overall performance of the BaSH fingerprint. This hybrid approach allows for activity prediction of compounds with only sparse HTSFPs due to the supporting effect from the structural fingerprint.