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

ABSTRACT: 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 .

SUBMITTER: Kumar N

PROVIDER: S-EPMC9306080 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The drug development process is a major challenge in the pharmaceutical industry since it takes a substantial amount of time and money to move through all the phases of developing of a new drug. One extensively used method to minimize the cost and time for the drug development process is computer-aided drug design (CADD). CADD allows better focusing on experiments, which can reduce the time and cost involved in researching new drugs. In this context, structure-based virtual screening (SBVS) is robust and useful and is one of the most promising in silico techniques for drug design. SBVS attempts to predict the best interaction mode between two molecules to form a stable complex, and it uses scoring functions to estimate the force of non-covalent interactions between a ligand and molecular target. Thus, scoring functions are the main reason for the success or failure of SBVS software. Many software programs are used to perform SBVS, and since they use different algorithms, it is possible to obtain different results from different software using the same input. In the last decade, a new technique of SBVS called consensus virtual screening (CVS) has been used in some studies to increase the accuracy of SBVS and to reduce the false positives obtained in these experiments. An indispensable condition to be able to utilize SBVS is the availability of a 3D structure of the target protein. Some virtual databases, such as the Protein Data Bank, have been created to store the 3D structures of molecules. However, sometimes it is not possible to experimentally obtain the 3D structure. In this situation, the homology modeling methodology allows the prediction of the 3D structure of a protein from its amino acid sequence. This review presents an overview of the challenges involved in the use of CADD to perform SBVS, the areas where CADD tools support SBVS, a comparison between the most commonly used tools, and the techniques currently used in an attempt to reduce the time and cost in the drug development process. Finally, the final considerations demonstrate the importance of using SBVS in the drug development process.

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

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