Chemical Biology and Drug Design
Chemical Biology and Drug Design
5 years ago

Importance of functional groups in predicting the activity of small molecule inhibitors for Bcl-2 and Bcl-xL

Importance of functional groups in predicting the activity of small molecule inhibitors for Bcl-2 and Bcl-xL
Ramasamy Sakthivel, M. Michael Gromiha, S. K. Rayala, Vishnupriya Kanakaveti
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/]. Developed scaffold-specific models for predicting Bcl-2 and Bcl-xL small molecule inhibitors. Explored the important functional groups affecting BH3 mimicking. Hydrogen bonding, flexibility, volume and surface area of atoms are vital for BH3 mimicking. Designed a Web server for predicting the activity of novel compounds. Screened novel compounds for all the seven scaffolds.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/cbdd.12952

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