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Review
. 2020 Sep 24;63(18):10170-10187.
doi: 10.1021/acs.jmedchem.0c00415. Epub 2020 May 12.

Essential Medicinal Chemistry of Essential Medicines

Marta Serafini  1 , Sarah Cargnin  1 , Alberto Massarotti  1 , Tracey Pirali  1 , Armando A Genazzani  1
Affiliations
Review

Essential Medicinal Chemistry of Essential Medicines

Marta Serafini et al. J Med Chem. .

Abstract

Since 1977, the World Health Organization publishes a list of essential medicines, i.e., those that satisfy the priority health care needs of the population and are selected with regard to disease prevalence and public health relevance, evidence of clinical efficacy, and safety, as well as comparative costs and cost-effectiveness. The Essential Medicines List (EML) is an invaluable tool for all countries to select those medicines that have an excellent risk/benefit ratio and that are reputed to be of pivotal importance to health. In the present perspective, we describe the chemical composition and the main features of the small molecules that are included in the EML, spanning from their origin, to their stereochemistry and measure of drug-likeness. Most and foremost, we wish to disseminate the importance of the EML, which can be both a helpful teaching tool in an ever-expanding world of medicines and an inspiration for those involved in pharmaceutical R&D.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Flowchart depicting the items on the EML and their exclusion to reach a unique, organic chemistry subset.
Figure 2
Figure 2
Classification of EML organic drugs according to their origin, ATC (1st level) codes, FDA approval year, and route of administration.
Figure 3
Figure 3
DT network of all approved drugs (A) and of EMs (B). The DT network is generated by using the known associations between drugs and targets extracted from the DrugBank database. As of March 2, 2020, DrugBank (version 5.1.5, released 2020-01-03) includes 2635 approved small molecule drugs and 1367 approved biologics. Additionally, 1148 nonredundant proteins (that are drug target/enzyme/transporter/carrier) sequences are linked to these drug entries. Small and big circles correspond to drugs and target proteins, respectively. A link is placed between a drug node and a target node if the protein is a known target of that drug. Drug nodes and connecting links are colored according to the ATC 1st level code of the drug. A bigger representation of the DT network is present in the Supporting Information.
Figure 4
Figure 4
Elements beyond CHON present in EMs.
Figure 5
Figure 5
Phosphorus-containing EMs.
Figure 6
Figure 6
Boron-containing EMs.
Figure 7
Figure 7
Frequency of selected functional groups found in the EML.
Figure 8
Figure 8
Frequency of heterocycles found in the EML. Heterocycles that are present in more than one EM.
Figure 9
Figure 9
Structures of EMs displaying PAINS.
Figure 10
Figure 10
Represented toxicophorics in the EML. Short-to-medium (s-to-m) chain fatty acids are carboxylic acids bound to a carbon chain with more than 3 atoms.
Figure 11
Figure 11
EMs containing a structural alert associated with a BBW due to IADRs. Structural alerts are highlighted in red.
Figure 12
Figure 12
Distribution of chiral centers in de novo, nature-inspired, and natural drugs. A more detailed version of Figure 12 is present in the Supporting Information.
Figure 13
Figure 13
Structures of the de novo, nature-inspired, and natural drugs that display the highest amount of stereocenters. Stereocenters are highlighted with a blue circle.
Figure 14
Figure 14
Structures of oral EMs that violate two or more of Lipinski’s parameters. Abbreviations: clogP, calculated logP; HBA, hydrogen bond acceptor; HBD, hydrogen bond donor; MW, molecular weight; clogP were extracted using DrugBank or ChemSpider databases.
Figure 15
Figure 15
(A) BBB scores in organic EMs, (B) stratified for their origin, and (C) CNS vs non-CNS drugs.
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