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

Abstract

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.

Decomposition of Small Molecules for Fragment-Based Drug Design

“…A similar request arose when using our recently proposed reverse fragment-based drug discovery (R-FBDD) [5,6]. R-FBDD proposes a simple and still useful way to infer the contributions of specific fragments to the interaction energy of the entire ligand with its target using scoring functions.…”

“…The above thinking is both close in spirit and complementary to the tools of the FBDD approach. One of the planned consumers of this decomposition is the Reverse Fragment-Based Drug Discovery (R-FBDD) approach [5,6], in which the contributions of individual non-overlapping fragments to the binding energy of the whole ligand are estimated based on the complex geometry by using, in particular, scoring functions.…”

Deciphering peptide-protein interactions via composition-based prediction: a case study with survivin/BIRC5

“…This assessment typically precedes the covalent connection of these fragments and the creation of the molecular structure of the drug. Further research is necessary to understand the physical basis of compatibility between functional groups in a protein and the extensive fragment libraries that organic synthesis can provide [68,69].…”