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Rational approaches to improving selectivity in drug design.

Huggins DJ, Sherman W, Tidor B - J. Med. Chem. (2012)

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge, CB2 0XZ, United Kingdom. djh210@cam.ac.uk

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In this review we highlight some recent examples of successful come at a cost in optimal target affinity, with greater gains requiring greater cost... complexity and expense... Thus, considerable benefit can result from faster and less computationally demanding methods of identifying the same effects... for a number of other drug targets... However, drug targets exist in a complex environment and effect of cell trafficking on drug molecules, it is also possible and presented real-world examples of how these principles have been successfully applied in achieving selectivity... of drug molecules is an area that is now being explored and has recently the nature of molecular scaffolds and the promiscuity of molecules

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Substrate envelope hypothesis.To achieve broad binding selectivityagainst an enzyme target and the collection of its functional mutants,a useful approach has been to develop inhibitors that bind withinand do not extend beyond the envelope created by the outer shape ofthe substrate (or a collection of substrates) bound to the activesite. The idea is illustrated in panels A–D, and an examplefrom HIV-1 protease is given in panels E–G. (A) The parenttarget protein is shown in orange outline and shading, and a boundsubstrate is shown in yellow with the substrate envelope indicatedby the yellow outline. (B) An inhibitor (green shading) that bindswithin the substrate envelope (yellow outline) binds not only theparent target (orange outline) but also a mutant (orange shading)that includes positions that protrude further into the active site(left side) and that retreat away from the site (right side). (C)A different inhibitor (green shading) that extends beyond the substrateenvelope (yellow outline) might make better interactions with theparent target (orange outline and shading) and even bind with higheraffinity than other inhibitors. (D) However, such an envelope-violatinginhibitor may bind poorly to protein mutants (orange shading) thatdiffer from the parent (orange outline) by protruding further intothe active site and introduce a potential clash with the inhibitor(left side, green hatching) or by retreating away from the activesite and remove a stabilizing interaction (right side, orange hatching).Interestingly, there is a preponderance of the “retreating”mutations over the “protruding” ones for HIV-1 protease,perhaps because of molecular plasticity issues. (E) An HIV-1 proteaseinhibitor66 that binds with high affinityto wild-type HIV-1 proteases as well as to mutants is shown to residewithin the substrate envelope (yellow surface) in its crystal structurein the protein complex (the protein has been removed for clarity).(F, G) HIV-1 protease inhibitor saquinavir from PDB entry 3OXC,184 which binds well to wild-type HIV-1 proteases but is susceptibleto resistance mutants, is shown to extend outside the substrate envelope(yellow surface) in its crystal structure (the protein has been removedfor clarity in panel F but is present in panel G, in which some sidechains associated with resistance mutations have been highlightedand labeled).
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fig7: Substrate envelope hypothesis.To achieve broad binding selectivityagainst an enzyme target and the collection of its functional mutants,a useful approach has been to develop inhibitors that bind withinand do not extend beyond the envelope created by the outer shape ofthe substrate (or a collection of substrates) bound to the activesite. The idea is illustrated in panels A–D, and an examplefrom HIV-1 protease is given in panels E–G. (A) The parenttarget protein is shown in orange outline and shading, and a boundsubstrate is shown in yellow with the substrate envelope indicatedby the yellow outline. (B) An inhibitor (green shading) that bindswithin the substrate envelope (yellow outline) binds not only theparent target (orange outline) but also a mutant (orange shading)that includes positions that protrude further into the active site(left side) and that retreat away from the site (right side). (C)A different inhibitor (green shading) that extends beyond the substrateenvelope (yellow outline) might make better interactions with theparent target (orange outline and shading) and even bind with higheraffinity than other inhibitors. (D) However, such an envelope-violatinginhibitor may bind poorly to protein mutants (orange shading) thatdiffer from the parent (orange outline) by protruding further intothe active site and introduce a potential clash with the inhibitor(left side, green hatching) or by retreating away from the activesite and remove a stabilizing interaction (right side, orange hatching).Interestingly, there is a preponderance of the “retreating”mutations over the “protruding” ones for HIV-1 protease,perhaps because of molecular plasticity issues. (E) An HIV-1 proteaseinhibitor66 that binds with high affinityto wild-type HIV-1 proteases as well as to mutants is shown to residewithin the substrate envelope (yellow surface) in its crystal structurein the protein complex (the protein has been removed for clarity).(F, G) HIV-1 protease inhibitor saquinavir from PDB entry 3OXC,184 which binds well to wild-type HIV-1 proteases but is susceptibleto resistance mutants, is shown to extend outside the substrate envelope(yellow surface) in its crystal structure (the protein has been removedfor clarity in panel F but is present in panel G, in which some sidechains associated with resistance mutations have been highlightedand labeled).

Mentions: For therapies to be usefulagainst rapidly mutating targets, they must avoid the developmentof resistance mutants that no longer bind the therapeutic molecule.Such cases are especially important in infectious disease and cancer,and such considerations are paramount in HIV. Application of the previouslydiscussed structure-based concepts first requires knowledge of all the potential targets, which can be daunting in thesesituations.The substrate envelope hypothesis elegantly avoids thisdifficulty for cases in which the target is an enzyme, by acknowledgingthat all targets must still bind and process substrate; mutants thatfail to process substrate are lethal, if the target is truly valid.The substrate envelope hypothesis is one implementation of the notionthat inhibitors sufficiently similar to substrate will bind to allenzyme variants capable of binding and processing substrates. Thespecific similarity criterion applied is that candidate inhibitors,when bound to the active site, must reside within and not extend beyondthe molecular envelope of substrates when productively bound at theactive site (Figure 7).


Rational approaches to improving selectivity in drug design.

Huggins DJ, Sherman W, Tidor B - J. Med. Chem. (2012)

Substrate envelope hypothesis.To achieve broad binding selectivityagainst an enzyme target and the collection of its functional mutants,a useful approach has been to develop inhibitors that bind withinand do not extend beyond the envelope created by the outer shape ofthe substrate (or a collection of substrates) bound to the activesite. The idea is illustrated in panels A–D, and an examplefrom HIV-1 protease is given in panels E–G. (A) The parenttarget protein is shown in orange outline and shading, and a boundsubstrate is shown in yellow with the substrate envelope indicatedby the yellow outline. (B) An inhibitor (green shading) that bindswithin the substrate envelope (yellow outline) binds not only theparent target (orange outline) but also a mutant (orange shading)that includes positions that protrude further into the active site(left side) and that retreat away from the site (right side). (C)A different inhibitor (green shading) that extends beyond the substrateenvelope (yellow outline) might make better interactions with theparent target (orange outline and shading) and even bind with higheraffinity than other inhibitors. (D) However, such an envelope-violatinginhibitor may bind poorly to protein mutants (orange shading) thatdiffer from the parent (orange outline) by protruding further intothe active site and introduce a potential clash with the inhibitor(left side, green hatching) or by retreating away from the activesite and remove a stabilizing interaction (right side, orange hatching).Interestingly, there is a preponderance of the “retreating”mutations over the “protruding” ones for HIV-1 protease,perhaps because of molecular plasticity issues. (E) An HIV-1 proteaseinhibitor66 that binds with high affinityto wild-type HIV-1 proteases as well as to mutants is shown to residewithin the substrate envelope (yellow surface) in its crystal structurein the protein complex (the protein has been removed for clarity).(F, G) HIV-1 protease inhibitor saquinavir from PDB entry 3OXC,184 which binds well to wild-type HIV-1 proteases but is susceptibleto resistance mutants, is shown to extend outside the substrate envelope(yellow surface) in its crystal structure (the protein has been removedfor clarity in panel F but is present in panel G, in which some sidechains associated with resistance mutations have been highlightedand labeled).
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3285144&req=5

fig7: Substrate envelope hypothesis.To achieve broad binding selectivityagainst an enzyme target and the collection of its functional mutants,a useful approach has been to develop inhibitors that bind withinand do not extend beyond the envelope created by the outer shape ofthe substrate (or a collection of substrates) bound to the activesite. The idea is illustrated in panels A–D, and an examplefrom HIV-1 protease is given in panels E–G. (A) The parenttarget protein is shown in orange outline and shading, and a boundsubstrate is shown in yellow with the substrate envelope indicatedby the yellow outline. (B) An inhibitor (green shading) that bindswithin the substrate envelope (yellow outline) binds not only theparent target (orange outline) but also a mutant (orange shading)that includes positions that protrude further into the active site(left side) and that retreat away from the site (right side). (C)A different inhibitor (green shading) that extends beyond the substrateenvelope (yellow outline) might make better interactions with theparent target (orange outline and shading) and even bind with higheraffinity than other inhibitors. (D) However, such an envelope-violatinginhibitor may bind poorly to protein mutants (orange shading) thatdiffer from the parent (orange outline) by protruding further intothe active site and introduce a potential clash with the inhibitor(left side, green hatching) or by retreating away from the activesite and remove a stabilizing interaction (right side, orange hatching).Interestingly, there is a preponderance of the “retreating”mutations over the “protruding” ones for HIV-1 protease,perhaps because of molecular plasticity issues. (E) An HIV-1 proteaseinhibitor66 that binds with high affinityto wild-type HIV-1 proteases as well as to mutants is shown to residewithin the substrate envelope (yellow surface) in its crystal structurein the protein complex (the protein has been removed for clarity).(F, G) HIV-1 protease inhibitor saquinavir from PDB entry 3OXC,184 which binds well to wild-type HIV-1 proteases but is susceptibleto resistance mutants, is shown to extend outside the substrate envelope(yellow surface) in its crystal structure (the protein has been removedfor clarity in panel F but is present in panel G, in which some sidechains associated with resistance mutations have been highlightedand labeled).
Mentions: For therapies to be usefulagainst rapidly mutating targets, they must avoid the developmentof resistance mutants that no longer bind the therapeutic molecule.Such cases are especially important in infectious disease and cancer,and such considerations are paramount in HIV. Application of the previouslydiscussed structure-based concepts first requires knowledge of all the potential targets, which can be daunting in thesesituations.The substrate envelope hypothesis elegantly avoids thisdifficulty for cases in which the target is an enzyme, by acknowledgingthat all targets must still bind and process substrate; mutants thatfail to process substrate are lethal, if the target is truly valid.The substrate envelope hypothesis is one implementation of the notionthat inhibitors sufficiently similar to substrate will bind to allenzyme variants capable of binding and processing substrates. Thespecific similarity criterion applied is that candidate inhibitors,when bound to the active site, must reside within and not extend beyondthe molecular envelope of substrates when productively bound at theactive site (Figure 7).

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge, CB2 0XZ, United Kingdom. djh210@cam.ac.uk

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

In this review we highlight some recent examples of successful come at a cost in optimal target affinity, with greater gains requiring greater cost... complexity and expense... Thus, considerable benefit can result from faster and less computationally demanding methods of identifying the same effects... for a number of other drug targets... However, drug targets exist in a complex environment and effect of cell trafficking on drug molecules, it is also possible and presented real-world examples of how these principles have been successfully applied in achieving selectivity... of drug molecules is an area that is now being explored and has recently the nature of molecular scaffolds and the promiscuity of molecules

Show MeSH
Related in: MedlinePlus