Virtual lock-and-key approach: The in silico revival of Fischer model by meansof molecular descriptors

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Abstract

In the last years the application of computational methodologies in the medicinal chemistry fields hasfound an amazing development. All the efforts were focused on the searching of new leads featuringa close affinity on a specific biological target. Thus, different molecular modeling approaches insimulation of molecular behavior for a specific biological target were employed. In spite of theincreasing reliability of computational methodologies, not always the designed lead, once synthesizedand screened, are suitable for the chosen biological target. To give another chance to thesecompounds, this work tries to resume the old concept of Fischer lock-and-key model. The same can bedone for the “re-purposing” of old drugs. In fact, it is known that drugs may have many physiologicaltargets, therefore it may be useful to identify them. This aspect, called “polypharmacology”, is knownto be therapeutically essential in the different treatments. The proposed protocol, the virtual lock-andkeyapproach (VLKA), consists in the “virtualization” of biological targets through the respectivelyknown inhibitors.In order to release a real lock it is necessary the key fits the pins of the lock. The molecular descriptorscould be considered as pins. A tested compound can be considered a potential inhibitor of a biologicaltarget if the values of its molecular descriptors fall in the calculated range values for the set of knowninhibitors. The proposed protocol permits to transform a biological target in a “lock model” starting fromits known inhibitors. To release a real lock all pins must fit. In the proposed protocol, it was supposed thatthe higher is the number of fit pins, the higher will be the affinity to the considered biological target.Therefore, each biological target was converted in a sequence of “weighted” molecular descriptor rangevalues (locks) by using the structural features of the known inhibitors. Each biological target lock wastested by performing a molecular descriptors “fitting” on known inhibitors not used in the modelconstruction (keys or test set).The results showed a good predictive capability of the protocol (confidence level 80%). This methodgives interesting and convenient results because of the user-defined descriptors and biological targetschoice in the process of new inhibitors discovery.
Original languageEnglish
Pages (from-to)4274-4280
Number of pages7
JournalEuropean Journal of Medicinal Chemistry
Volume46
Publication statusPublished - 2011

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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