Machine intelligence-driven framework for optimized hit selection in virtual screening

Virtual screening (VS) aids in prioritizing unknown bio-interactions between compounds and protein targets for empirical drug discovery. In standard VS exercise, roughly 10% of top-ranked molecules exhibit activity when examined in biochemical assays, which accounts for many false positive hits, making it an arduous task. Attempts for conquering false-hit rates were developed through either ligand-based or structure-based VS separately; however, nonetheless performed remarkably well. Here, we present an advanced VS framework—automated hit identification and optimization tool (A-HIOT)—comprises chemical space-driven stacked ensemble for identification and protein space-driven deep learning architectures for optimization of an array of specific hits for fixed protein receptors. A-HIOT implements numerous open-source algorithms intending to integrate chemical and protein space leading to a high-quality prediction. The optimized hits are the selective molecules which we retrieve after extreme refinement implying chemical space and protein space modules of A-HIOT. Using CXC chemokine receptor 4, we demonstrated the superior performance of A-HIOT for hit molecule identification and optimization with tenfold cross-validation accuracies of 94.8% and 81.9%, respectively. In comparison with other machine learning algorithms, A-HIOT achieved higher accuracies of 96.2% for hit identification and 89.9% for hit optimization on independent benchmark datasets for CXCR4 and 86.8% for hit identification and 90.2% for hit optimization on independent test dataset for androgen receptor (AR), thus, shows its generalizability and robustness. In conclusion, advantageous features impeded in A-HIOT is making a reliable approach for bridging the long-standing gap between ligand-based and structure-based VS in finding the optimized hits for the desired receptor. The complete resource (framework) code is available at https://gitlab.com/neeraj-24/A-HIOT. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13321-022-00630-7.