RESUMEN
Targeting the challenging tumors lacking explicit markers and predictors for chemosensitivity is one of the major impediments of the current cancer armamentarium. Triple-negative breast cancer (TNBC) is an aggressive and challenging molecular subtype of breast cancer, which needs astute strategies to achieve clinical success. The pro-survival B-cell lymphoma 2 (BCL-2) overexpression reported in TNBC plays a central role in deterring apoptosis and is a promising target. Here, we propose three novel BH4 mimetic small molecules, SM396, a covalent binder, and two non-covalent binders, i.e., SM216 and SM949, which show high binding affinity (nM) and selectivity, designed by remodeling the existing BCL-2 chemical space. Our mechanistic studies validate the selectivity of the compounds towards cancerous cells and not on normal cells. A series of functional assays illustrated BCL-2-mediated apoptosis in the tumor cells as a potent anti-cancerous mechanism. Moreover, the compounds exhibited efficacious in vivo activity as single agents in the MDA-MB-231 xenograft model (at nanomolar dosage). Overall, these findings depict SM216, SM396, and SM949 as promising leads, pointing to the clinical translation of these compounds in targeting triple-negative breast cancer.
RESUMEN
In the era of big data, the interplay of artificial and human intelligence is the demanding job to address the concerns involving exchange of decisions between both sides. Drug discovery is one of the key sources of the big data, which involves synergy among various computational methods to achieve a clinical success. Rightful acquisition, mining and analysis of the data related to ligand and targets are crucial to accomplish reliable outcomes in the entire process. Novel designing and screening tactics are necessary to substantiate a potent and efficient lead compounds. Such methods are emphasized and portrayed in the current review targeting protein-ligand and protein-protein interactions involved in various diseases with potential applications.
Asunto(s)
Antineoplásicos/química , Antivirales/química , Dengue/tratamiento farmacológico , Diseño de Fármacos , Flavonoides/química , Neoplasias/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Antivirales/uso terapéutico , Biología Computacional/métodos , ARN Polimerasas Dirigidas por ADN/antagonistas & inhibidores , ARN Polimerasas Dirigidas por ADN/genética , ARN Polimerasas Dirigidas por ADN/metabolismo , Dengue/metabolismo , Dengue/virología , Descubrimiento de Drogas/métodos , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Flavonoides/uso terapéutico , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Mapeo de Interacción de Proteínas , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismoRESUMEN
BACKGROUND: 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. OBJECTIVE: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Asunto(s)
Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Algoritmos , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-ActividadRESUMEN
Evasion of apoptosis owing to aberrant expression of Bcl-2 (B-cell lymphoma-2) anti-apoptotic proteins is a promising hallmark of cancer. These proteins are associated with resistance to chemotherapy and radiation. Currently available QSAR models are limited to a set of inhibitors corresponding to a particular chemical scaffold, and unified models are required to identify the differential specificity of diverse compounds toward inhibiting these targets. In this study, we predicted the factors driving differential activity and specificity implementing multiplexed QSAR analysis for a dataset of 1,649 reported inhibitors of Bcl-2 (B-cell lymphoma-2) and Bcl-xL (B-cell lymphoma-extra large). We developed QSAR models for seven diverse scaffolds and critically analyzed the chemical space with coupling factors. The correlation values of QSAR models for Bcl-2 and Bcl-xL range from 0.95 to 0.985. The MAE and sMAPE of the models were in the range of 0.052-5.4 nm and 0.41%-10%, respectively, signifying model robustness. The crucial descriptors and moieties accounting for the activity were benchmarked against experimentally determined binding patterns. The comprehensive analysis made in the study explores latent features of the chemical space in a broad perspective. Further, we have developed a user-friendly Web server for predicting a specific/dual inhibitor of Bcl-2 and Bcl-xL [http://www.iitm.ac.in/bioinfo/APPLE/].