Classification of scaffold-hopping approaches

The general goal of drug discovery is to identify novel compounds that are active against a preselected biological target with acceptable pharmacological properties defined by marketed drugs. Scaffold hopping has been widely applied by medicinal chemists to discover equipotent compounds with novel backbones that have improved properties. In this article we classify scaffold hopping into four major categories, namely heterocycle replacements, ring opening or closure, peptidomimetics and topology-based hopping. We review the structural diversity of original and final scaffolds with respect to each category. We discuss the advantages and limitations of small, medium and large-step scaffold hopping. Finally, we summarize software that is frequently used to facilitate different kinds of scaffold-hopping methods.     

SHAFTS: a hybrid approach for 3D molecular similarity calculation. 2. Prospective case study in the discovery of diverse p90 ribosomal S6 protein kinase 2 inhibitors to suppress cell migration

We described a prospective application of ligand-based virtual screening program SHAFTS to discover novel inhibitors for p90 ribosomal S6 protein kinase 2 (RSK2). Taking the putative 3D conformations of two weakly binding RSK2 NTKD inhibitors as query templates, SHAFTS was used to perform 3D similarity based virtual screening because of a lack of crystal structure of RSK2 protein, thus leading to the identification of several novel scaffolds that would have been missed by conventional 2D fingerprint methods. The most potent hit compounds show low micromolar inhibitory activities against RSK2. In particular, one of the hit compounds exhibits potent antimigration activity against the MDA-MB-231 tumor cell. The results exemplified SHAFTS' application in active enrichment and scaffold hopping, which is of general interest for lead identification in drug discovery endeavors and also provides novel scaffolds that lay the foundation for uncovering new RSK2 regulatory mechanisms.     

Structure‐guided Discovery of a Novel Non‐peptide Inhibitor of Dengue Virus NS2B–NS3 Protease

Dengue fever is a fast emerging epidemic‐prone viral disease caused by dengue virus serotypes 1‐4. NS2B–NS3 protease of dengue virus is a validated target to develop antiviral agents. A major limitation in developing dengue virus protease inhibitors has been the lack of or poor cellular activity. In this work, we extracted and refined a pharmacophore model based on X‐ray crystal structure and predicted binding patterns, followed by a three‐dimensional flexible database filtration. These output molecules were screened according to a docking‐based protocol, leading to the discovery of a compound with novel scaffold and good cell‐based bioactivity that has potential to be further optimized. The discovery of this novel scaffold by combination of in silico methods suggests that structure‐guided drug discovery can lead to the development of potent dengue virus protease inhibitors.     

In silico studies on recreational drugs: 3D quantitative structure activity relationship prediction of classified and de novo designer benzodiazepines

Currently, increasing availability and popularity of designer benzodiazepines (DBZDs) constitutes a primary threat to public health. To assess this threat, the biological activity/potency of DBZDs was investigated using in silico studies. Specific Quantitative Structure Activity Relationship (QSAR) models were developed in Forge™ for the prediction of biological activity (IC₅₀) on the γ-aminobutyric acid A receptor (GABA-AR) of previously identified classified and unclassified DBDZs. A set of new potential ligands resulting from scaffold hopping studies conducted with MOE^® was also evaluated. Two generated QSAR models (i.e. 3D-field QSAR and RVM) returned very good performance statistics (r² = 0.98 [both] and q² = 0.75 and 0.72, respectively). The DBZDs predicted to be the most active were flubrotizolam, clonazolam, pynazolam and flucotizolam, consistently with what reported in literature and/or drug discussion fora. The scaffold hopping studies strongly suggest that replacement of the pendant phenyl moiety with a five-membered ring could increase biological activity and highlight the existence of a still unexplored chemical space for DBZDs. QSAR could be of use as a preliminary risk assessment model for (newly) identified DBZDs, as well as scaffold hopping for the creation of computational libraries that could be used by regulatory bodies as support tools for scheduling procedures.     

Discovery of novel small molecule inhibitors of dengue viral NS2B-NS3 protease using virtual screening and scaffold hopping

By virtual screening, compound 1 was found to be active against NS2B-NS3 protease (IC(50) = 13.12 ± 1.03 μM). Fourteen derivatives (22) of compound 1 were synthesized, leading to the discovery of four new inhibitors with biological activity. In order to expand the chemical diversity of the inhibitors, small-molecule-based scaffold hopping was performed on the basis of the common scaffold of compounds 1 and 22. Twenty-one new compounds (23, 24) containing quinoline (new scaffold) were designed and synthesized. Protease inhibition assays revealed that 12 compounds with the new scaffold are inhibitors of NS2B-NS3 protease. Taken together, 17 new compounds were discovered as NS2B-NS3 protease inhibitors with IC(50) values of 7.46 ± 1.15 to 48.59 ± 3.46 μM, and 8 compounds belonging to two different scaffolds are active to some extent against DENV based on luciferase reporter replicon-based assays. These novel chemical entities could serve as lead structures for discovering therapies against DENV.     

QSAR studies in the discovery of novel type-II diabetic therapies

Introduction: Type-II diabetes mellitus (T2DM) is a complex chronic disease that represents a major therapeutic challenge. Despite extensive efforts in T2DM drug development, therapies remain unsatisfactory. Currently, there are many novel and important antidiabetic drug targets under investigation by many research groups worldwide. One of the main challenges to develop effective orally active hypoglycemic agents is off-target effects. Computational tools have impacted drug discovery at many levels. One of the earliest methods is quantitative structure–activity relationship (QSAR) studies. QSAR strategies help medicinal chemists understand the relationship between hypoglycemic activity and molecular properties. Hence, QSAR may hold promise in guiding the synthesis of specifically designed novel ligands that demonstrate high potency and target selectivity.

Areas covered: This review aims to provide an overview of the QSAR strategies used to model antidiabetic agents. In particular, this review focuses on drug targets that raised recent scientific interest and/or led to successful antidiabetic agents in the market. Special emphasis has been made on studies that led to the identification of novel antidiabetic scaffolds.

Expert opinion: Computer-aided molecular design and discovery techniques like QSAR have a great potential in designing leads against complex diseases such as T2DM. Combined with other in silico techniques, QSAR can provide more useful and rational insights to facilitate the discovery of novel compounds. However, since T2DM is a complex disease that includes several faulty biological targets, multi-target QSAR studies are recommended in the future to achieve efficient antidiabetic therapies.     

Molecular field analysis (MFA) and other QSAR techniques in development of phosphatase inhibitors

Phosphatases are well known drug targets for diseases such as diabetes, obesity and other autoimmune diseases. Their role in cancer is due to unusual expression patterns in different types of cancer. However, there is strong evidence for selective targeting of phosphatases in cancer therapy. Several experimental and in silico techniques have been attempted for design of phosphatase inhibitors, with focus on diseases such as diabetes, inflammation and obesity. Their utility for cancer therapy is limited and needs to be explored vastly. Quantitative Structure Activity relationship (QSAR) is well established in silico ligand based drug design technique, used by medicinal chemists for prediction of ligand binding affinity and lead design. These techniques have shown promise for subsequent optimization of already existing lead compounds, with an aim of increased potency and pharmacological properties for a particular drug target. Furthermore, their utility in virtual screening and scaffold hopping is highlighted in recent years. This review focuses on the recent molecular field analysis (MFA) and QSAR techniques, directed for design and development of phosphatase inhibitors and their potential use in cancer therapy. In addition, this review also addresses issues concerning the binding orientation and binding conformation of ligands for alignment sensitive QSAR approaches.     

When analoging is not enough: scaffold discovery in medicinal chemistry

Importance of the field: As an integral part of lead generation and optimization, scaffold discovery has broad implications in drug discovery. Currently available chemical scaffolds might be inadequate to provide drug-like ligands for new targets such as phosphatases and protein–protein interactions and therapeutically useful chemical space needs to be continuously explored. New scaffolds are often desired to overcome major hurdles (e.g., potency plateau, selectivity, pharmacokinetics, etc.) in lead generation and optimization. Timely discovery of proof-of-concept compounds facilitates target validation, diversifies clinical candidates and improves the overall success rate of drug discovery.

Areas covered in this review: This analysis discusses the strategies involved in finding new scaffolds (i.e., fragment-, ligand- and structure-based design) and their applications (e.g., improve potency/selectivity, multiple ligand design, protein–protein interactions, etc.) in drug discovery.

What the reader will gain: The readers will learn the strategies involved in scaffold design and the problems that they solve. They will also gain the understanding of the circumstances suitable for using scaffold design.

Take home message: Scaffold is defined by the authors as a biological target dependent concept. Therapeutically useful scaffolds are limited and the identification of new scaffolds is sometimes required to overcome major optimization hurdles. However, depending on the promiscuity of the binding pocket of the target and the validity of the optimization protocol, finding better scaffolds can be a challenging task. Several strategies in scaffold discovery have emerged or matured owing to recent trends such as pursuit of targets from new proteomic families, lack of validated targets, advances in synthesis and biological assays and adoption of in vitro activity-driven screening paradigms.     

Design,synthesis, and molecular docking study of 3H‐imidazole[4,5‐c]pyridine derivatives as CDK2 inhibitors

A novel series of imidazo[4,5‐c]pyridine‐based CDK2 inhibitors were designed from the structure of CYC202 via scaffold hopping strategy. These compounds were synthesized and biologically evaluated for their CDK2 inhibitory and in vitro anti‐proliferation potential against cancer cell lines. Several compounds exhibited potent CDK2 inhibition with IC₅₀ values of less than 1 µM. The most potent compound 5b showed excellent CDK2 inhibitory (IC₅₀ = 21 nM) and in vitro anti‐proliferation activity against three different cell lines (HL60, A549, and HCT116). The molecular docking and dynamic studies portrayed the potential binding mechanism between 5b and CDK2, and several key interactions between them were observed, which would be the reason for its potent CDK2 inhibitory and anti‐proliferation activities. Therefore, the pyridin‐3‐ylmethyl moiety would serve as an excellent pharmacophore for the development of novel CDK2 inhibitors for targeted anti‐cancer therapy.

     

药物分子设计的策略：论药效团和骨架迁越

药物分子是由药效团和结构骨架构成的，药效团是由不连续的离散的原子、基团或片断所构成，但需结合在分子骨架上，形成具体的分子。骨架具有连续性，相同的药效团附着在不同的分子骨架上，构成了作用于同一靶标而结构多样的化合物。骨架依据受体的柔性和可塑性形成了“杂乱性”的空间。显示了受体结合部位的杂乱性。杂乱性越大，可容纳的配体分子的结构多样性就越多，意味着结构修饰与变换的余地大，成药的机会多。由苗头化合物演化成先导物，进而优化成候选药物，这由化合物变革成安全、有效、稳定、可控的药物过程就是保持药效团、变换分子骨架、修饰基团和边链的过程。结构骨架的变化可分为3个层次：以电子等排原理变换骨架结构；以优势结构为导向变换骨架结构；以结构一活性演化的方式变换骨架结构，即骨架迁越。骨架迁越的目的是改善分子的物化、药代、稳定性和赋予分子的结构新颖性。该文以实例阐述了骨架变换的方法与技巧。     

Structure‐based virtual screening toward the discovery of novel inhibitors of the DNA repair activity of the human apurinic/apyrimidinic endonuclease 1

The DNA repair activity of human apurinic/apyrimidinic endonuclease 1 (APE1) has been recognized as a promising target for the development of small‐molecule inhibitors to be used in combination with anticancer agents. In an attempt to identify novel inhibitors of APE1, we present a structure‐based virtual screening (SBVS) study based on molecular docking analysis of the compounds of NCI database using the GOLD 5.1.0 (Genetic Optimization for Ligand Docking) suite of programs. Compounds selected in this screening were tested with a fluorescence‐based APE1 endonuclease activity assay. Two compounds ( 37 and 41 ) were able to inhibit the multifunctional enzyme APE1 in the micromolar range, while compound 22 showed inhibitory effects at nanomolar concentrations. These results were confirmed by a plasmid DNA nicking assay. In addition, the potential APE1 inhibitors did not affect the cell viability of non‐tumor MCF10A cells. Overall, compounds 22 , 37, and 41 appear to be important scaffolds for the design of novel APE1 inhibitors and this study highlights the relevance of in silico‐based approaches as valuable tools in drug discovery.     

In silico screening for identification of novel HIV-1 integrase inhibitors using QSAR and docking methodologies

Human immunodeficiency virus-1 integrase (HIV-1 IN) is an important target for HIV-1 infection. Here, shape based screening workflow was designed to discover novel inhibitors against HIV-1 IN protein. The best docked conformation of highly active curcumine molecule 32 (Gupta et al. Mol Diversity 15:733–750, 2011) was used as a template for screening of drug-like databases. The screened molecules were filtered out using toxicity studies. The in silico inhibitory activity of screened molecules against HIV-1 IN was predicted using 2D (Gupta et al. Curr Comput Aided Drug Des 9:141–150, 2013) and 3D (Gupta et al. Mol Diversity 15:733–750, 2011) QSAR models. Subsequently, putative binding modes of these molecules were investigated using different docking algorithms. Some of the molecules exhibited similar poses in both the algorithms and fulfilled the criteria for the best docking pose. Eventually, 11 novel scaffolds were identified from the designed workflow. These screened molecules could be potential hits against HIV-1 IN. These combined techniques were facilitated here to get different scaffolds with good ADMET, QSAR, and docking predictions, which can be further explored for lead optimization purpose. Besides, these scaffolds can be a good starting point for researchers for designing of new molecules against HIV-1 IN.     

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 t he 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.     

Discovery of 2‐(3,4‐dialkoxyphenyl)‐2‐(substituted pyridazin‐3‐yl)acetonitriles as phosphodiesterase 4 inhibitors with anti‐neuroinflammation potential based on three‐dimensional quantitative structure–activity relationship study

Phosphodiesterase 4 (PDE4) inhibitors with potential activities for CNS disorders provide a new therapeutic strategy for depression. To discover PDE4 inhibitors with anti‐neuroinflammation activities, reliable three‐dimensional quantitative structure‐activity relationship (3D‐QSAR) models on our previous reported catecholic PDE4 inhibitors was built with a statistically significant cross‐validated coefficient (q²), conventional coefficient (r²), and good predictive capabilities based on the molecular docking results, using comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) methods. Based on the analysis of CoMFA and CoMSIA contour maps, a series of 2‐(3,4‐dialkoxyphenyl)‐2‐(substituted pyridazin‐3‐yl) acetonitriles 16a–i was designed and synthesized. Among these compounds, compound 16a exhibited good inhibitory activities toward PDE4B1 and PDE4D7 with mid‐nanomolar IC₅₀ values and potential anti‐neuroinflammation activity in BV‐2 cells. Docking simulation of compound 16a in the PDE4 catalytic domain activity pocket revealed that compound 16a maybe assumed a “V‐shaped” conformation, extending the side chain to S‐pocket.     

Synthesis,Biological Evaluation,and Molecular Simulation of Chalcones and Aurones as Selective MAO‐B Inhibitors

A series of chalcones and aurones were synthesized and evaluated in vitro as monoamine oxidase inhibitors (MAOi). Our results show that aurones, which had not been previously reported as MAOi, are MAO‐B inhibitors. Thus, both families inhibited selectively the B isoform of MAO in the micromolar range, offering novel scaffolds for the design of new and potent MAO inhibitors. The main structural requirements for their activity were characterized with the aid of 3D‐QSAR and docking studies.     

Multiple determinants for selective inhibition of apicomplexan calcium-dependent protein kinase CDPK1

Diseases caused by the apicomplexan protozoans Toxoplasma gondii and Cryptosporidium parvum are a major health concern. The life cycle of these parasites is regulated by a family of calcium-dependent protein kinases (CDPKs) that have no direct homologues in the human host. Fortuitously, CDPK1 from both parasites contains a rare glycine gatekeeper residue adjacent to the ATP-binding pocket. This has allowed creation of a series of C3-substituted pyrazolopyrimidine compounds that are potent inhibitors selective for CDPK1 over a panel of human kinases. Here we demonstrate that selectivity is further enhanced by modification of the scaffold at the C1 position. The explanation for this unexpected result is provided by crystal structures of the inhibitors bound to CDPK1 and the human kinase c-SRC. Furthermore, the insight gained from these studies was applied to transform an alternative ATP-competitive scaffold lacking potency and selectivity for CDPK1 into a low nanomolar inhibitor of this enzyme with no activity against SRC.     

QSAR of phytochemicals for the design of better drugs

Introduction: Phytochemicals have been the single most prolific source of leads for the development of new drug entities from the dawn of the drug discovery. They cover a wide range of therapeutic indications with a great diversity of chemical structures. The research fraternity still believes in exploring the phytochemicals for new drug discovery. Application of molecular biological techniques has increased the availability of novel compounds that can be conveniently isolated from natural sources. Combinatorial chemistry approaches are being applied based on phytochemical scaffolds to create screening libraries that closely resemble drug-like compounds. In silico techniques like quantitative structure–activity relationships (QSAR), pharmacophore and virtual screening are playing crucial and rate accelerating steps for the better drug design in modern era.

Areas covered: QSAR models of different classes of phytochemicals covering different therapeutic areas are thoroughly discussed in the review. Further, the authors have enlisted all the available phytochemical databases for the convenience of researchers working in the area.

Expert opinion: This review justifies the need to develop more QSAR models for the design of better drugs from phytochemicals. Technical drawbacks associated with phytochemical research have been lessened, and there are better opportunities to explore the biological activity of previously inaccessible sources of phytochemicals although there is still the need to reduce the time and cost involvement in such exercise. The future possibilities for the integration of ethnopharmacology with QSAR, place us at an exciting stage that will allow us to explore plant sources worldwide and design better drugs.     

Insights from structural analysis of cFMS/inhibitor complexes: common interactions via three structurally dissimilar scaffolds

A small-molecule drug discovery effort can benefit from having several chemical series. Where multiple series are not available, it is often the goal of a project to find novel scaffolds. Structural studies of ligand/protein complexes provide important information on the interactions driving binding. By generalizing these, it is possible to find molecules lacking in similarity in their connectivity yet retaining the ability to interact with the same target protein. Our studies on inhibitors of the cFMS tyrosine kinase provide a dramatic example of three different chemical series that make the same key interactions with the target protein. Collectively, these structural data provide a striking example of the pharmacophore hypothesis at work. In addition, they should prompt one to employ a broad approach when attempting scaffold hopping or any search for a novel series. It is clear that molecules that bind with similar interactions to a target need not possess 2-dimensional molecular similarity.