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Considerations of Protein Subpockets in Fragment-Based Drug Design.

ABSTRACT: While the fragment-based drug design approach continues to gain importance, gaps in the tools and methods available in the identification and accurate utilization of protein subpockets have limited the scope. The importance of these features of small molecule-protein recognition is highlighted with several examples. A generalized solution for the identification of subpockets and corresponding chemical fragments remains elusive, but there are numerous advancements in methods that can be used in combination to address subpockets. Finally, additional examples of approaches that consider the relative importance of small-molecule co-dependence of protein conformations are highlighted to emphasize an increased significance of subpockets, especially at protein interfaces.

SUBMITTER: Bartolowits M

PROVIDER: S-EPMC5464946 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Considerations of Protein Subpockets in Fragment-Based Drug Design.

Bartolowits Matthew M Davisson V Jo VJ

Chemical biology & drug design 20150831 1

While the fragment-based drug design approach continues to gain importance, gaps in the tools and methods available in the identification and accurate utilization of protein subpockets have limited the scope. The importance of these features of small molecule-protein recognition is highlighted with several examples. A generalized solution for the identification of subpockets and corresponding chemical fragments remains elusive, but there are numerous advancements in methods that can be used in c ...[more]

PMID: 26307335

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Project description: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.

Dataset Information

Considerations of Protein Subpockets in Fragment-Based Drug Design.

Publications

Considerations of Protein Subpockets in Fragment-Based Drug Design.

Similar Datasets

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