Assessing How Residual Errors of Scoring Functions Correlate to Ligand Structural Features.

Scoring functions (SFs) are ubiquitous tools for early stage drug discovery. However, their accuracy currently remains quite moderate. Despite a number of successful target-specific SFs appearing recently, up until now, no ideas on how to systematically improve the general scope of SFs have been formulated. In this work, we hypothesized that the specific features of ligands, corresponding to interactions well appreciated by medicinal chemists (e.g., hydrogen bonds, hydrophobic and aromatic interactions), might be responsible, in part, for the remaining SF errors. The latter provides direction to efforts aimed at the rational and systematic improvement of SF accuracy. In this proof-of-concept work, we took a CASF-2016 coreset of 285 ligands as a basis for comparison and calculated the values of scores for a representative panel of SFs (including AutoDock 4.2, AutoDock Vina, X-Score, NNScore2.0, ΔVina RF20, and DSX). The residual error of linear correlation of each SF value, with the experimental values of affinity and activity, was then analyzed in terms of its correlation with the presence of the fragments responsible for certain medicinal chemistry defined interactions. We showed that, despite the fact that SFs generally perform reasonably, there is room for improvement in terms of better parameterization of interactions involving certain fragments in ligands. Thus, this approach opens a potential way for the systematic improvement of SFs without their significant complication. However, the straightforward application of the proposed approach is limited by the scarcity of reliable available data for ligand-receptor complexes, which is a common problem in the field.

In Silico Structure-Based Approach for Group Efficiency Estimation in Fragment-Based Drug Design Using Evaluation of Fragment Contributions.

The notion of a contribution of a specific group in an organic molecule's property and/or activity is both common in our thinking and is still not strictly correct due to the inherent non-additivity of free energy with respect to molecular fragments composing a molecule. The fragment- based drug discovery (FBDD) approach has proven to be fruitful in addressing the above notions. The main difficulty of the FBDD, however, is in its reliance on the low throughput and expensive experimental means of determining the fragment-sized molecules binding. In this article we propose a way to enhance the throughput and availability of the FBDD methods by judiciously using an in silico means of assessing the contribution to ligand-receptor binding energy of fragments of a molecule under question using a previously developed in silico Reverse Fragment Based Drug Discovery (R-FBDD) approach. It has been shown that the proposed structure-based drug discovery (SBDD) type of approach fills in the vacant niche among the existing in silico approaches, which mainly stem from the ligand-based drug discovery (LBDD) counterparts. In order to illustrate the applicability of the approach, our work retrospectively repeats the findings of the use case of an FBDD hit-to-lead project devoted to the experimentally based determination of additive group efficiency (GE)-an analog of ligand efficiency (LE) for a group in the molecule-using the Free-Wilson (FW) decomposition. It is shown that in using our in silico approach to evaluate fragment contributions of a ligand and to estimate GE one can arrive at similar decisions as those made using the experimentally determined activity-based FW decomposition. It is also shown that the approach is rather robust to the choice of the scoring function, provided the latter demonstrates a decent scoring power. We argue that the proposed approach of in silico assessment of GE has a wider applicability domain and expect that it will be widely applicable to enhance the net throughput of drug discovery based on the FBDD paradigm.