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Lagunin A.A., Filimonov D.A., Poroikov V.V.

Institute of Biomedical Chemistry RAMS, Russia, Moscow

Edited by Alexander Kos 15.10.02

Each biologically active compound reveals a wide variety of biological actions in biological systems (human organisms,  animals, in vivo and in vitro assays). It is practically impossible to study each compound in all tests currently available. Therefore, the ability to select compounds with required types of biological activity and without unwanted adverse effects and toxicity is very desirable.

The software PASS (Prediction of Activity Spectra for Substances) and PharmaExpert was developed toward this purpose. PASS predicts biological activity spectra on the basis of structural formulae of chemical compounds. The biological activity of compounds is predicted on the basis of structure-activity relationships of known biological active substances presented in the training set. PASS 1.602 training set includes 45649 substances. PASS 1.602 can predict 1043 different types of biological activity including pharmacological effects, biochemical mechanisms, carcinogenicity, mutagenicity and teratogenicity. The mean prediction of accuracy in leave one out cross-validations of PASS is about 85%.

PharmaExpert determines the existing relationships between pharmacological effects and biochemical mechanisms. The current version of PharmaExpert covers 1587 mechanisms of action, 418 pharmaco-therapeutical effects and 2664 types of relationships between them.  


The above screenshot shows the relationship of the activities in the area 1. With the button 2 you can toggle the hierarchy looking once at mechanisms, or at effects.

How can I select compounds which have the required biological activities without having unwanted effects?  

Using the search functionality (1)  you can select the desired activities (2), and you can define the search criteria, you also can search by Pi (predicted inactivity - useful for adverse effects). In the result window you will find the actual values (3), the compound IDs (4) and highlighting the ID will display the corresponding structure (5).

How can I find a profile of important activities for a class of compounds?   

The "Statistic" window in PharmaExpert lets you sort the activities by name, or by numbers. For this group of known AChEIs the most important activities are given below.

No	Pa>Pi	Pa>30%	Pa>50%	Pa>70%	Types of Activity
1	134	134	124	86	Nootropic
2	133	129	110	66	Cognition disorders treatment
3	134	120	89	52	Cholinergic
4	130	119	84	49	Acetylcholinesterase inhibitor
5	95	95	84	41	Antiamyloidogenic
6	86	86	85	38	Antieczematic atopic
7	73	71	40	32	Dependence treatment
8	86	86	72	26	Neurotransmitter agonist
9	91	73	40	24	Miotic
10	63	63	53	23	Hepatotoxic
11	76	76	65	22	Hydrolase inhibitor
12	80	80	73	19	Antiurolithic
13	58	58	45	18	Immunomodulator (HIV)
14	52	32	19	17	Butyrylcholinesterase inhibitor
15	67	44	19	17	Beta amyloid precursor protein antagonist
16	118	118	46	14	Alzheimer's disease treatment
17	91	91	71	13	Adrenaline release inhibitor
18	90	90	57	12	Alpha 1b adrenoreceptor antagonist
19	74	74	54	11	Apoptosis antagonist
20	44	44	22	10	Fibrinogen receptor antagonist

We have to emphasize that we have no proof yet, if such a selection correspond to the real situation of a drug.

I want to develop new drugs with new structural features, or a new skeleton. How can PASS help me, if its prediction is dependent on a training set of known compounds?

We have two approaches to this problem. (1) We described the use of profiles, and clustering with neural networks, see slides 17 and 18 from a presentation at an ACS conference.

(2) You can use PharmaExpert. 

In the screenshot above we show the PASS parameters for the activity "Antiparkinsonian" (1) that were calculated, and (2) you see the complete relationship of "Antiparkinsonian" to other effects.  If your desired activity would be "Adrenaline Agonist" you might not find any prediction for it because your structure class and this activity was not covered in the training set. You might find that your compound is "Antiparkinsonian". The relationship of effects and mechanism tells you that this compound might have your desired activity "Adrenaline Agonist". Through the relationship of effects you bridge the gap that occurs because many structure classes were not investigated for a certain activity. There is still the chance that your structure class is completely new, and PASS might miss it. However, the MNA descriptors of PASS are sensitive to small fragments, and your structure class must be so new that it does not contain any small similar fragments to already observed compounds. 

PASS and PharmaExpert can give you an early indication, obtained cheap and fast if your compound might be a good or bad drug candidate!