First Principles DFT Studies of Metal-Based Biological and Biomimetic Systems - Metallic Systems: A Quantum Chemist's Perspective - page 15

20

A
C
D
E

15

10

ξ

5

0

10 12 14 16

(a) (b) Reaction coordinate ξ (Å)

FIGURE 1.5 (See color insert.) (a).Backbone.atoms.and.their.centers.of.mass.(transpar-
ent.and.solid.blue.spheres,.respectively).deining.the.reaction.coordinate.ξ..(b).Free-energy.
proiles.(kcal/mol).for. A - E ..Small.arrows.indicate.the.free-energy.minima,.and.the.yellow.
bar.shows.the.minor.groove.width.of.DNA-HMG.

opening.the.minor.groove.incurs.a.high.free-energy.cost.(Δ G .~.7-8.kcal.mol −1 ).for.
A .and. B .which.substantially.increases.for. C .(Δ G .~.15.kcal.mol −1 ),.which.is.higher.
for.dinuclear.drugs.than.for.canonical.B.DNA.(Δ G .~.5.kcal.mol −1 ).and.for.the.cor-
responding.cisplatin-DNA.adduct.(Δ G .~.0.kcal.mol −1 ). 126
Thus,. the. formation. of. diplatinum. drug-DNA. adducts. may. signiicantly. affect.
the.binding.of.excision.repair.enzymes.and.other.proteins.involved.in.the.cytotoxic.
activity.of.common.Pt.drugs..Subsequently,.this.process.could.lead.to.a.different.cel-
lular.response.and,.in.turn,.to.a.lower.resistance.and.cross-resistance.with.respect.to.
cisplatin. 126 .Although.the.development.of.drug.resistance.is.a.highly.complex.mecha-
nism,.our.indings.provide.an.additional.rationale.for.the.improved.cytotoxic.activity.
of.these.compounds.in.cell.lines.resistant.to.cisplatin.

1.3.3 c atalytic m echaniSm of m etallo β -l actamaSeS
β-Lactams.are.the.most.widespread.antibiotics.on.the.market..They.have.exerted.a.
large.evolutionary.pressure.on.bacteria,.triggering.sophisticated.resistance.mecha-
nisms.. Among. them,. the. most. used. is. the. expression. of. β-lactamases,. hydrolases.
which. use. different. protein. scaffolds. and. catalytic. architectures. to. inactivate.
β-lactam.drugs. 156
β-Lactamases.from.classes.A,.C,.and.D.are.the.serine.hydrolases,.whereas.class.
B.β-lactamases.are.characterized.by.the.presence.of.Zn.ions.bound.to.their.active.
sites. 157 . Metallo. β-lactamases. (MβLs),. despite. not. being. as. ubiquitous. as. serine.
β-lactamases,.hydrolyze.all.kinds.of.β-lactam.antibiotics,.including.the.latest.gener-
ation.of.carbapenems.(Scheme.1.1)..MβLs.are.increasingly.spreading.among.patho-
genic.bacteria.in.the.clinical.setting.and.are.resistant.to.all.current.clinical.inhibitors.
on.the.market. 158-161 .Thus,.understanding.their.function.at.the.molecular.level.is.of.
paramount.importance.for.designing.effective.drugs.