To determine physicochemical and toxicity properties using free online services.

Aim: To determine physicochemical and toxicity properties using free online services.

Theory:

    Bringing a pharmaceutical drug to the market is a long term process that costs sixty-five thousand crores of Indian rupees. One promising approach for improving the efficiency and productivity of early discovery in the pharmaceutical industry and academia is Virtual screenings that use computer-based methods. The ultimate final goal of Virtual screenings is to identify drug like molecules with the best chance to become an effective medicine.

    It has been demonstrated that early estimation of ADME and Toxicology (ADMET) parameters in the discovery phase reduces drastically the fraction of pharmacokinetics related failure in the clinical phases. Lipinski's rule (Rule of five) states that, in general, an orally active drug has no more than one violation of the following criteria:

1. Hydrogen bond donors (N-H and O-H bonds) not more than 5 (5 x 1).
2. Hydrogen bond acceptors (all N- or H-atoms) not more than 10 (5 x 2).
3. Molecular mass less than 500 (5 x 100) daltons.
4. An octanol-water partition coefficient log P not greater than 5 (5 x 1).

    Nonetheless, drug like molecules predicted by Lipinski's rule has spawned many extensions including Ghose's rule; Lead likeness and bioavailability rules.

    Accurate prediction of log P is highly important for the pharmaceutical industry since it limits costly and time-consuming experiments to measure log P required to optimize pharmacodynamic and pharmacokinetic properties. MLOGP, ALOGP, Consensus log P and ALOGP98 are among the best methods for online log P prediction. Another type of large variety of ADMET parameters is derived from molecular structure. Some user-friendly, open access and most intuitive procedures to derive ADMET parameters are reported below:

1. SwissADME (http://www.swissadme.ch)

Free online services for the determination of physicochemical properties, lipophilicity, water solubility, pharmacokinetics, drug likeness and medicinal chemistry.

2. Molinspiration (http://www.molinspiration.com/cgi-bin/properties)

Free online services for the calculation of important molecular properties, and bioactivity score for the most important drug targets.

3. OsirisProperty Explorer (http://www.organic-chemistry.org/prog/peo)

Free online services for the toxicity risk assessment, physicochemical properties, and drug likeness.

4. pkCSM (http://biosig.unimelb.edu.au/pkcsm/prediction)

Free online services for predicting pharmacokinetic and toxicity properties.

Procedure:

1. Open the online tool from URL.
2. Use a molecular sketcher based on Marvin JS/JMS or use SMILES string to draw a structure of the compound.
3. Run the job to predict the ADMET parameter of a compound.

Example:

Diazepam: Physicochemical and toxicity properties prediction.

IUPAC Name: 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2-one

Mol. Wt.: 284.74

Mol. Formula: C₁6H₁3CIN₂O

Smiles: CN1C₂=C(C=C(Cl)C=C₂)C(= NCC₁ = O)C₁=CC=CC=C₁

1. SwissADME (http://www.swissadme.ch)

2. Molinspiration (http://www.molinspiration.com/cgi-bin/properties)

3. OsirisProperty Explorer (http://www.organic-chemistry.org/prog/peo)

Osiris calculations of compounds(Diazepam):

Toxicity level:

    Mutagenic: --

    Tumorigenic: --

    Irritant: +

    Reproductive Effect: -

Osiris Calculations:
    Druglikeness: 5.98

    Drug-Score: 0.15

Abbr.: + Drug-conform behavirous, - Toxic effects, ± Undesired effect

4. pkCSM (http://biosig.unimelb.edu.au/pkcsm/prediction)

Result:

The physicochemical and toxicity properties using free online services are shown above.

Reference:

• SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 2017, 7, 42717.
• Ertl P, Rohde B, Selzer P. Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties. J. Med. Chem. 2000, 43, 3714-3717.
• Pires DEV, Blundell TL, Ascher DB. pkCSM: predicting small-molecule pharmaco kinetic and toxicity properties using graph-based signatures. J. Med. Chem. 2015, 58 (9), 4066-4072.