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.
Lingua originaleEnglish
pagine (da-a)4274-4280
Numero di pagine7
RivistaEuropean Journal of Medicinal Chemistry
Volume46
Stato di pubblicazionePublished - 2011

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Molecular Models
Computer Simulation
Polypharmacology
Molecular modeling
Pharmaceutical Chemistry
Pharmaceutical Preparations
Lead
isofenphos
Virtualization

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cita questo

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title = "Virtual lock-and-key approach: The in silico revival of Fischer model by meansof molecular descriptors",
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.",
keywords = "Biological target, Drugs re-purposing, Inhibitor, Lock-and-key, Molecular descriptors",
author = "Almerico, {Anna Maria} and Antonino Lauria and Marco Tutone",
year = "2011",
language = "English",
volume = "46",
pages = "4274--4280",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier Masson SAS",

}

TY - JOUR

T1 - Virtual lock-and-key approach: The in silico revival of Fischer model by meansof molecular descriptors

AU - Almerico, Anna Maria

AU - Lauria, Antonino

AU - Tutone, Marco

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

KW - Biological target

KW - Drugs re-purposing

KW - Inhibitor

KW - Lock-and-key

KW - Molecular descriptors

UR - http://hdl.handle.net/10447/57828

M3 - Article

VL - 46

SP - 4274

EP - 4280

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -