Hao Liu

Song Li, Song Ke, Chenxing Yang et al.

Gonadotrophin-releasing hormone receptor (GnRH1R) is a promising therapeutic target for the treatment of uterine diseases. To date, several GnRH1R antagonists are available in clinical investigation without satisfying multiple property constraints. To fill this gap, we aim to develop a deep learning-based framework to facilitate the effective and efficient discovery of a new orally active small-molecule drug targeting GnRH1R with desirable properties. In the present work, a ligand-and-structure combined model, namely LS-MolGen, was firstly proposed for molecular generation by fully utilizing the information on the known active compounds and the structure of the target protein, which was demonstrated by its superior performance than ligand- or structure-based methods separately. Then, a in silico screening including activity prediction, ADMET evaluation, molecular docking and FEP calculation was conducted, where ~30,000 generated novel molecules were narrowed down to 8 for experimental synthesis and validation. In vitro and in vivo experiments showed that three of them exhibited potent inhibition activities (compound 5 IC50 = 0.856 nM, compound 6 IC50 = 0.901 nM, compound 7 IC50 = 2.54 nM) against GnRH1R, and compound 5 performed well in fundamental PK properties, such as half-life, oral bioavailability, and PPB, etc. We believed that the proposed ligand-and-structure combined molecular generative model and the whole computer-aided workflow can potentially be extended to similar tasks for de novo drug design or lead optimization.

Jiaxi Zhang, Liwei Ni, Shenggen Zheng et al.

Boolean matching is significant to digital integrated circuits design. An exhaustive method for Boolean matching is computationally expensive even for functions with only a few variables, because the time complexity of such an algorithm for an n-variable Boolean function is $O(2^{n+1}n!)$. Sensitivity is an important characteristic and a measure of the complexity of Boolean functions. It has been used in analysis of the complexity of algorithms in different fields. This measure could be regarded as a signature of Boolean functions and has great potential to help reduce the search space of Boolean matching. In this paper, we introduce Boolean sensitivity into Boolean matching and design several sensitivity-related signatures to enhance fast Boolean matching. First, we propose some new signatures that relate sensitivity to Boolean equivalence. Then, we prove that these signatures are prerequisites for Boolean matching, which we can use to reduce the search space of the matching problem. Besides, we develop a fast sensitivity calculation method to compute and compare these signatures of two Boolean functions. Compared with the traditional cofactor and symmetric detection methods, sensitivity is a series of signatures of another dimension. We also show that sensitivity can be easily integrated into traditional methods and distinguish the mismatched Boolean functions faster. To the best of our knowledge, this is the first work that introduces sensitivity to Boolean matching. The experimental results show that sensitivity-related signatures we proposed in this paper can reduce the search space to a very large extent, and perform up to 3x speedup over the state-of-the-art Boolean matching methods.