Bioinformatics Tools Training Program

The process involved in the research, discovery and development of drugs is characterized by high
extensive and complexcostlinked to scientific and technological innovations, and it is necessary to
study and verify the progress of research carried out in the field that results in patent applications.
Based on this principle, the pharmaceutical industry applies high investments in bioprospecting
research, although it is aware that research on new drugs is a high-risk market. Thus, drug
designstrategies began to include molecular recognition studies in biological systems, assuming
great importance, as they became fundamental bases for the understanding of properties such as
potency, affinity and selectivity and structure-activity. And thus, the biotechnological tools
associated with medicinal chemistry methods have gained a prominent role in the development of
new molecules with biological activity.

In order to avoid this failure, a set of ADME/Toxin silico filters was implemented in most
pharmaceutical companies, aiming to discard substances, in the discovery phase, that are likely to
fail later. This strategy tends to reduce the probability of failure, reducing time and resources used
in research. And so, several softwares were developed that perform different analysis of molecules,
inferring on the physicochemical, pharmacokinetic and pharmacodynamic parameters in the
development stage.

Accessing http://www.swissadme.ch in a web browser displays directly the submission page of
SwissADME, where molecules to be estimated for ADME, physicochemistry, drug-likeness,
pharmacokinetics and medicinal chemistry friendliness properties can be input.

Physicochemical Properties
Simple molecular and physicochemical descriptors like molecular weight (MW), molecular
refractivity (MR), count of specific atom types and polar surface area (PSA) are compiled in this
section. The values are computed with OpenBabel9, version 2.3.0. The PSA is calculated using the fragmental technique called topological polar surface area (TPSA), considering sulfur and
phosphorus as polar atoms. This has proven a useful descriptor in many models and rules to quickly
estimate some ADME properties.

Lipophilicity
The partition coefficient between n-octanol and water (log Po/w) is the classical descriptor for
Lipophilicity. It has a dedicated section in SwissADME due to the critical importance of this
physicochemical property for pharmacokinetics drug discovery. Many computational methods for
log Po/w estimation were developed with diverse performance on various chemical sets.

Pharmacokinetics
Specialized models, whose predictions are compiled in the Pharmacokinetics section, evaluate
individual ADME behaviours of the molecule under investigation.
The predictions for passive human gastrointestinal absorption (HIA) and blood-brain barrier (BBB)
permeation both consist in the readout of the BOILED-Egg model, an intuitive graphical
classification model, which can be displayed in the SwissADME result page by clicking the red
button appearing below the sketcher when all input molecules have been processed.
The knowledge about compounds being substrate or non-substrate of the permeability glycoprotein
(P-gp, suggested the most important member among ATP-binding cassette transporters or ABCtransporters) is key to appraise active efflux through biological membranes, for instance from the
gastrointestinal wall to the lumen or from the brain.

Drug-likeness
As defined earlier, “drug-likeness” assesses qualitatively the chance for a molecule to become an
oral drug with respect to bioavailability. Drug-likeness was established from structural or
physicochemical inspections of development compounds advanced enough to be considered oral
drug-candidates. This notion is routinely employed to perform filtering of chemical libraries to
exclude molecules with properties most probably incompatible with an acceptable pharmacokinetics
profile. This SwissADME section gives access to five different rule-based filters, with diverse
ranges of properties inside of which the molecule is defined as drug-like.

Medicinal Chemistry
The purpose of this section is to support medicinal chemists in their daily drug discovery
endeavours. Two complementary pattern recognition methods allow for identification of potentially
problematic fragments. PAINS (for pan assay interference compounds, a.k.a. frequent hitters or promiscuous compounds) are molecules containing substructures showing potent response in assays
irrespective of the protein target.