GenUI: interactive and extensible open source software platform for de novo molecular generation and cheminformatics.

Many contemporary cheminformatics methods, including computer-aided de novo drug design, hold promise to significantly accelerate and reduce the cost of drug discovery. Thanks to this attractive outlook, the field has thrived and in the past few years has seen an especially significant growth, mainly due to the emergence of novel methods based on deep neural networks. This growth is also apparent in the development of novel de novo drug design methods with many new generative algorithms now available. However, widespread adoption of new generative techniques in the fields like medicinal chemistry or chemical biology is still lagging behind the most recent developments. Upon taking a closer look, this fact is not surprising since in order to successfully integrate the most recent de novo drug design methods in existing processes and pipelines, a close collaboration between diverse groups of experimental and theoretical scientists needs to be established. Therefore, to accelerate the adoption of both modern and traditional de novo molecular generators, we developed Generator User Interface (GenUI), a software platform that makes it possible to integrate molecular generators within a feature-rich graphical user interface that is easy to use by experts of diverse backgrounds. GenUI is implemented as a web service and its interfaces offer access to cheminformatics tools for data preprocessing, model building, molecule generation, and interactive chemical space visualization. Moreover, the platform is easy to extend with customizable frontend React.js components and backend Python extensions. GenUI is open source and a recently developed de novo molecular generator, DrugEx, was integrated as a proof of principle. In this work, we present the architecture and implementation details of GenUI and discuss how it can facilitate collaboration in the disparate communities interested in de novo molecular generation and computer-aided drug discovery.

Profiling and analysis of chemical compounds using pointwise mutual information.

Pointwise mutual information (PMI) is a measure of association used in information theory. In this paper, PMI is used to characterize several publicly available databases (DrugBank, ChEMBL, PubChem and ZINC) in terms of association strength between compound structural features resulting in database PMI interrelation profiles. As structural features, substructure fragments obtained by coding individual compounds as MACCS, PubChemKey and ECFP fingerprints are used. The analysis of publicly available databases reveals, in accord with other studies, unusual properties of DrugBank compounds which further confirms the validity of PMI profiling approach. Z-standardized relative feature tightness (ZRFT), a PMI-derived measure that quantifies how well the given compound's feature combinations fit these in a particular compound set, is applied for the analysis of compound synthetic accessibility (SA), as well as for the classification of compounds as easy (ES) and hard (HS) to synthesize. ZRFT value distributions are compared with these of SYBA and SAScore. The analysis of ZRFT values of structurally complex compounds in the SAVI database reveals oligopeptide structures that are mispredicted by SAScore as HS, while correctly predicted by ZRFT and SYBA as ES. Compared to SAScore, SYBA and random forest, ZRFT predictions are less accurate, though by a narrow margin (AccZRFT = 94.5%, AccSYBA = 98.8%, AccSAScore = 99.0%, AccRF = 97.3%). However, ZRFT ability to distinguish between ES and HS compounds is surprisingly high considering that while SYBA, SAScore and random forest are dedicated SA models, ZRFT is a generic measurement that merely quantifies the strength of interrelations between structural feature pairs. The results presented in the current work indicate that structural feature co-occurrence, quantified by PMI or ZRFT, contains a significant amount of information relevant to physico-chemical properties of organic compounds.

QSAR-derived affinity fingerprints (part 1): fingerprint construction and modeling performance for similarity searching, bioactivity classification and scaffold hopping.

An affinity fingerprint is the vector consisting of compound's affinity or potency against the reference panel of protein targets. Here, we present the QAFFP fingerprint, 440 elements long in silico QSAR-based affinity fingerprint, components of which are predicted by Random Forest regression models trained on bioactivity data from the ChEMBL database. Both real-valued (rv-QAFFP) and binary (b-QAFFP) versions of the QAFFP fingerprint were implemented and their performance in similarity searching, biological activity classification and scaffold hopping was assessed and compared to that of the 1024 bits long Morgan2 fingerprint (the RDKit implementation of the ECFP4 fingerprint). In both similarity searching and biological activity classification, the QAFFP fingerprint yields retrieval rates, measured by AUC (~ 0.65 and ~ 0.70 for similarity searching depending on data sets, and ~ 0.85 for classification) and EF5 (~ 4.67 and ~ 5.82 for similarity searching depending on data sets, and ~ 2.10 for classification), comparable to that of the Morgan2 fingerprint (similarity searching AUC of ~ 0.57 and ~ 0.66, and EF5 of ~ 4.09 and ~ 6.41, depending on data sets, classification AUC of ~ 0.87, and EF5 of ~ 2.16). However, the QAFFP fingerprint outperforms the Morgan2 fingerprint in scaffold hopping as it is able to retrieve 1146 out of existing 1749 scaffolds, while the Morgan2 fingerprint reveals only 864 scaffolds.