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.

In the drug design process, a frequent task is the decomposition of small molecules into fragments. There exist a number of approaches and methods to break molecules into fragments. However, a method that allows the decomposition of molecules into non-overlapping fragments that is meaningful in terms of medicinal chemistry is absent, and in this work, we present a new simple approach for the decomposition of molecules—MedChemFrag. It aims to break drug-like molecules into a set of rings and linkers, which are close to the perception of “fragments” by medicinal chemists. In contrast to most previous efforts aimed at breaking molecules using retrosynthetic feasible rules, our approach strives to preserve the functional groups, which may reveal the specific interaction pattern, e.g., the amide groups.

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.

Background. The authors present the Russian experience of clinical use of a gene therapy drug in the treatment of progressive Duchenne muscular dystrophy through exon 53 skipping, using the only drug of this class registered in Russia, viltolarsen (Viltepso®), as an example. It is approved for the treatment of patients with amenable DMD gene deletions, however, real-world clinical efficacy across different age groups requires further clarification. Aim. To evaluate the efficacy of viltolarsen in real world clinical practice in the Russian Federation, depending on age at treatment initiation and functional status. Materials and methods. The study included 48 patients aged 1.83 to 17.58 years with deletion mutations correctable by exon 53 skipping (del 43–52, 45–52, 48–52, 49–52, 50–52, 52) treated with viltolarsen. Patients were stratified into 4 cohorts: 1) ambulatory patients who initiated therapy under 4 years of age (n = 4); 2) ambulatory patients who initiated therapy at 4–7 years of age (n = 20); 3) ambulatory patients who initiated therapy at ≥8 years of age (n = 19); 4) non-ambulatory patients at therapy initiation (n = 5). Standard functional tests, pulmonary function and cardiac function were assessed. Mean treatment duration was 2.1 ± 1.1 years. Results. Viltolarsen, depending on the age of therapy initiation, improves and/or stabilizes functional parameters in ambulatory children with Duchenne muscular dystrophy, and significantly prolongs the age of ability to walk independently: 18 out of 19 patients in cohort 3 at high risk of loss of ambulation (mean age 11.6 ± 1.6 years old) maintained the ability to walk, whereas control group patients lost this function at 8.9 ± 0.9 years old (p 0.01). Loss of ambulation in the studied cohort was associated with sharp deviations from typical child development: extreme obesity, growth spurts, cardiorespiratory problems. In patients who started therapy after loss of independent ambulation, no marked deterioration in mean cardiac function and respiratory function was observed during the follow-up period. No signs of clinically significant renal function deterioration during the follow-up period, as determined by cystatin C levels, were observed (0.896 ± 0.027 (n = 26) versus 0.941 ± 0.021 (n = 47), p 0.05). Conclusion. Preliminary study results have shown that viltolarsen improves and/or stabilizes functional outcomes in ambulatory children with DMD, significantly prolongs the age of independent ambulation, and stabilizes cardiorespiratory parameters in non-ambulatory patients. Early initiation of comprehensive multidisciplinary management of patients with Duchenne muscular dystrophy is required as a mandatory basis for pathogenetic therapy.