Prediction of substrates for Cytochrome P450s

Today is the day we talk about Cytochromes; how important they are, what can you do with them using Althotas Virtual Laboratory and why haven’t you done anything about them yet?

Humor aside, cytochromes P450s are the second most important iron containing compounds of our body (second only to hemoglobin of course)..They play a role in diverse biochemical finctions i.e. apoptosis, however, most importantly they play a role in the metabolism of many endogenous and exogenous compounds. The property of cytochrome P450 superfamily to mainly act as oxidizing enzymes has given them the name of mixed function monoxygenases. The oxidizing ability ultimately leads to the conversion of reactants to more soluble /polar substances, as is seen in case of lipophilic drugs, steroid hormones and prostaglandins. Cytochrome P450s might play a vital role in the deactivation of drugs, or in some instances their conversion to more active compounds. They have been indicated as the major player in the modification and clearance of almost 75% of the prescribed drugs (Guengerich, 2008).

CYPs in Althotas

The question arises that what are the benefits of predicting substrates for CYP450s. The answer is simple, when such a large number of drugs undergo a CYP mediated metabolic pathway, it is likely that metabolism related drug interactions occur that might be detrimental to the body’s functions. For example, if one drug is involved in the inhibition of the CYP-mediated metabolism of another drug, there are high chances that the other drug will accumulate inside the cell to toxic levels.  This is where in-silico prediction tools like Althotas come in handy. You can analyze a large number of drugs and test them for their binding affinity to CYPs. Cross matching substrates to a single type of CYP can then be carefully analyzed in further in-vitro experiments. Althotas is hosting SVM predictions and docking experiments for numerous members of the CYP450 family 1,2 and 3. The members of these families are closely linked in drug metabolism.

Substrate prediction of CYP450 against thirteen different drugs. Cross matching substates for a single type of CYP could be contraindicated. This example is discussed in detail in the tutorial.

The use of substrate prediction for CYPs is not just limited to the drugs that are already in use. You can use Althotas to get useful predictions in the discovery of experimental therapeutics. The SVM prediction and docking experiments can be run in bulk to all CYPs in one go which will give you speedy and accurate results.

Reference (s):

Guengerich FP (January 2008). “Cytochrome p450 and chemical toxicology”. Chem. Res. Toxicol. 21 (1): 70–83

 

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