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Abstract
Most pharmaceutical substances interact with several or even many molecular targets in the organism, determining the complex profiles of their biological activity. Moreover, due to biotransformation in the human body, they form one or several metabolites with different biological activity profiles. Therefore, the development and rational use of novel drugs requires the analysis of their biological activity profiles, taking into account metabolism in the human body. In silico methods are currently widely used for estimating new drug-like compounds’ interactions with pharmacological targets and predicting their metabolic transformations. In this study, we consider the estimation of the biological activity profiles of organic compounds, taking into account the action of both the parent molecule and its metabolites in the human body. We used an external dataset that consists of 864 parent compounds with known metabolites. It is shown that the complex assessment of active pharmaceutical ingredients’ interactions with the human organism increases the quality of computer-aided estimates. The toxic and adverse effects showed the most significant difference: reaching 0.16 for recall and 0.14 for precision.
Highlights
The discovery and development of new drugs is a topical biomedical research task due to the unmet needs in treating many human disorders and insufficient efficacy and safety of the launched medicines [1]
As we found in some cases, metabolic schemes are different in ChEMBL, DrugBank, and Metabolite databases, scrupulous collection of information and the prior manual curation of the metabolism data is necessary to obtain a more reliable computational assessment of the integral biological activity profiles
It is known that the biological activity of drug metabolites may differ from those of the parent compounds, which sometimes leads to the rejection of the launched medicines from the market
Summary
The discovery and development of new drugs is a topical biomedical research task due to the unmet needs in treating many human disorders and insufficient efficacy and safety of the launched medicines [1]. The “magic bullet” concept proposed by the Nobel laureate Paul Ehrlich at the beginning of the XX century [2] is substituted by the network pharmacology approach [3]. Such changes were essential because most pharmaceutical agents interact with multiple molecular targets in the organism, producing desirable and adverse pharmacological effects. Due to the unsuspected toxicity of drug metabolites, many launched pharmaceuticals have been withdrawn from the market; some examples include troglitazone, tienilic acid, ximelagatran, zomepirac, etc. Troglitazone was approved for medical purposes as an antidiabetic and anti-inflammatory drug in 1997 and withdrawn in 2000 due to the hepatotoxicity mainly produced by its reactive metabolites [5]
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