Automatic Tailoring and Transplanting: A Practical Method that Makes Virtual Screening More Useful

Abstract

Docking-based virtual screening of large compound libraries has been widely applied to lead discovery in structure-based drug design. However, subsequent lead optimizations often rely on other types of computational methods, such as de novo design methods. We have developed an automatic method, namely automatic tailoring and transplanting (AutoT&T), which can effectively utilize the outcomes of virtual screening in lead optimization. This method detects suitable fragments on virtual screening hits and then transplants them onto a lead compound to generate new ligand molecules. Binding affinities, synthetic feasibilities, and drug-likeness properties are considered in the selection of final designs. In this study, our AutoT&T program was tested on three different target proteins, including p38 MAP kinase, PPAR-α, and Mcl-1. In the first two cases, AutoT&T was able to produce molecules identical or similar to known inhibitors with better potency than the given lead compound. In the third case, we demonstrated how to apply AutoT&T to design novel ligand molecules from scratch. Compared to the solutions generated by other two de novo design methods, i.e., LUDI and EA-Inventor, the solutions generated by AutoT&T were structurally more diverse and more promising in terms of binding scores in all three cases. AutoT&T also completed the assigned jobs more efficiently than LUDI and EA-Inventor by several folds. Our AutoT&T method has certain technical advantages over de novo design methods. Importantly, it expands the application of virtual screening from lead discovery to lead optimization and thus may serve as a valuable tool for many researchers.

AutoGrow4: an open-source genetic algorithm for de novo drug design and lead optimization

“…Over the years, a number of programs have been developed to assist with de novo drug design [75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90][91]. A comprehensive review is beyond the scope of this article, but a few programs, summarized in Table 3, warrant specific mention.…”

Computational methods for drug design and discovery: focus on China

“…Active hits obtained from HTS typically exhibit low or medium level of activities, which are subsequently modified to improve their potency, selectivity, and to incorporate other favorable physical chemical properties. Recently, Li et al devised a method called AutoT&T (automatic tailoring and transplanting) [55], which can capture strong binding fragments of hits from VS outputs and transplant them into a lead compound with novel and optimized chemical structure. It means that the approach does not need to perform sampling of the possible combinations of fragments and conformations of the resulting molecules during structural operations, making it more efficient than conventional de novo design methods.…”

Fragment Informatics and Computational Fragment‐Based Drug Design: An Overview and Update

“…Inspired by the idea of the BREED method, Wang's group developed an automatic method named automatic tailoring and transplanting (AutoT&T) that can effectively utilize the results of virtual screening in fragment‐based lead optimization . AutoT&T identifies suitable fragments from virtual screening hits and then transplants them onto a predefined lead compound to generate new ligand molecules with improved binding affinities.…”