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Basili, Serena (2009) Computational Approaches for the Rational Design of Novel Topoisomerase I Poisons as Potential Anticancer Drugs. [Ph.D. thesis]

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Abstract (english)

Topoisomerase I (TopoI) is an essential DNA-targeting enzyme which alters the supercoiling of DNA through a concerted process of breaking and rejoining of a DNA strand, thereby controlling the DNA topology required for replication and transcription. TopoI mediates relaxation of supercoiled DNA by creating a transient single-strand break in the DNA duplex that originates from a transesterification reaction involving a nucleophilic attack by the active-site tyrosine (Tyr723) hydroxyl group on a DNA phosphodiester bond situated at the site of cleavage. The resulting 3'-phosphotyrosine enzyme-DNA complex (“covalent binary complex” or “cleavable complex”) is then reversed, after DNA relaxation through strand passage, when the released 5'-OH of the nicked strand reattacks the phosphotyrosine intermediate in a second transesterification reaction. These events result in the relaxation of the DNA structure, which is required during transcription or replication.
TopoI is a specific target for the pentacyclic alkaloid Camptothecin (CPT), which was first isolated in 1966 from extracts of Camptotheca Acuminata, and its derivatives, known as TopoI poisons.
These molecules block DNA religation, thus converting TopoI into a DNA-damaging agent. In the presence of a TopoI poison a ternary complex between DNA, an intercalator and topoisomerase is formed. Such a ternary complex is more stable than the DNA-TopoI associate, which may lead to an enhanced lifetime of the initially cleaved DNA. As a consequence of the misalignment of the free 5-hydroxyl group and the scissile tyrosine-DNA bond due to the presence of the drug, the religation of the broken strand cannot take place, i.e. the strand break persists. This activates a complex sequence of intacellular responses, that ultimately lead to cell death by apoptosis. Therefore, molecules which form such stabilized ternary complexes with DNA and TopoI exhibit a high potential as DNA-targeting anticancer drugs.
Camptothecin was early shown to be clinically problematic because, in addition to its negligible water solubility, its active “ring-closed” ?-hydroxylactone form is rapidly converted under physiological conditions to the open carboxylate form, which is inactive and readily binds to human serum albumin, making it inaccessible for cellular uptake.
To date, only two semisynthetic analogs of Camptothecin (Topotecan and Irinotecan) have been approved by FDA for the clinical treatment of the ovarian, small cell-lung and colon cancers.
Solving crystal structures of Top1 in complex both with Camptothecin and Topotecan and with structurally different molecules (indolocarbazoles and indoloquinolines) has significantly increased the amount of structural information about the interaction between the Top1-DNA binary complex and the poison molecule. This encouraged the application of structure-based drug design to investigate
and rationalize the activity of Top1 poisons and to rationally design new potential anticancer drugs. Thus, we considered the possibility to find a new pharmacophore exploiting all the available crystal structures to find the set of structural features which are in common to all of the five TopoI poisons.
In order to obtain new derivatives easier to be synthesized while maintaining the pharmacophoric features required for the formation of a stable TopoI-DNA-poison ternary complex, the synthesis of simplified CPT derivatives was proposed. It is possible to suppose that a pentacyclic scaffold is not necessarily required for a molecule to effectively bind the TopoI-DNA binary complex, providing that it maintains an aromatic planar system for the intercalation and appropriate functional groups to interact with specific residues of TopoI. On the basis of this assumption, several scaffolds were designed and docking studies with different search algorithms were performed to predict the ability of simplified analogs to form stable ternary complex with TopoI and DNA.
Moreover, we performed a molecular docking analysis on a series of new 5-substituted CPT derivatives to achieve more insight into the interactions of the new compounds with the binary TopoI-DNA complex. The introduction of substituents in position 5 of the CPT scaffold results in derivatives with reduced cytotoxic potency compared with the reference drugs. In general, the presence of a small lipophilic substituent is well tolerated while the modification with hydrophilic groups results in reduced affinity for the binding site. The presence of bulky groups is detrimental for cytotoxic potency because of the loss of important stabilizing interactions. Computational results indicated as a general feature that the 5-?-epimer is better tolerated in the binding site compared to the 5-?-epimer, resulting in higher biological activity.
Recently, a new series of 16a-thio-CPT derivatives has been synthesized. Biological assays for this class of compounds revealed that 16a-thio-CPT derivatives have higher anticancer activity compared to their oxo-analogs, both in vitro and in vivo, and are potent TopoI inhibitors. In order to find a rational explanation to their remarkable activity, a computational analysis was performed, both for predicting elements of their pharmacokinetic behavior and for describing their binding mode through a docking analysis. Docking results did not reveal striking differences between thio- and oxo-derivatives in terms of binding mode and docking score. On the contrary, the predicted values for features such as lipophilicity, water solubility and cell permeability indicated that these properties may be responsible for a significantly different pharmacokinetic profile for the two classes of compounds.
For the docking analysis of 5-substituted and 16a-thio CPT derivatives we used the quantum mechanics (QM)-polarized ligand docking (QPLD) protocol (Schrödinger software suite) with an aim to improve accuracy in docking calculations. Traditional docking methods employ an approximated physical chemistry-based representation of protein-ligand interactions, obtaining charges from a molecular mechanics force-field. The QPLD protocol uses an ab initio methodology to calculate ligand charges within the protein environment, thus taking into account the charge polarization induced by the protein environment.
The work on 5-substituted and 16a-thio CPT derivative was sponsored by the pharmaceutical company Indena S.p.A., Milano, Italy. The work was carried out in collaboration with the group of Professor Arturo Battaglia (Centro Nazionale Richerche Bologna, Italy) for the synthesis of the compounds, and with the group of Professor Franco Zunino (Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy), that was concerned with biological assays.

Abstract (italian)

La Topoisomerasi I eucariotica (TopoI) è un enzima essenziale che modifica il grado di superavvolgimento del DNA mediante un processo di rottura e successiva ricongiunzione di uno dei due filamenti del DNA, regolandone lo stato topologico richiesto nei processi di replicazione e di trascrizione.
Il rilassamento del DNA superavvolto indotto dalla TopoI avviene attraverso la rottura transitoria di un filamento per mezzo di una reazione di transesterificazione. Quest'ultima coinvolge l'attacco nucleo lo da parte del gruppo ossidrilico di un residuo di tirosina (Tyr723) del sito attivo dell'enzima ad un legame fosfodiesterico del DNA a livello del sito di taglio, con formazione di un complesso covalente 3'-fosfotirosina TopoI-DNA (noto anche come cleavable complex). La rotazione del filamento tagliato intorno a quello intatto rende possibile il rilassamento della molecola di DNA. Il complesso binario covalente subisce in seguito un attacco nucleofilo a livello della fosfotirosina da parte dell'estremità libera 5'-OH del lamento rotto, che permette la riformazione del legame fosfodiesterico.
La TopoI è il target specifico dell'alcaloide pentaciclico Camptotecina (CPT), isolato per la prima volta nel 1966 dalla corteccia di Camptotheca Acuminata, e dei suoi derivati, noti come veleni di TopoI.
Queste molecole bloccano il processo di ricongiunzione del filamento di DNA tagliato, convertendo la TopoI in un agente dannoso per il DNA stesso. Queste molecole si intercalano tra le basi del DNA a livello del sito di taglio dando luogo alla formazione di un complesso ternario con la TopoI e il DNA. La maggiore stabilità del complesso ternario rispetto al complesso binario TopoI-DNA risulta in un aumento del tempo di vita del DNA tagliato. Poiché la presenza del veleno induce il disallineamento dell'estremità libera 5'-OH del filamento rotto con il legame fosfotirosinico, il processo di ricongiunzione non può avvenire. Questo porta all'attivazione di una serie complessa di segnali intracellulari, il cui risultato ultimo è la morte della cellula per apoptosi. Di conseguenza, le molecole in grado di formare complessi ternari stabili hanno attività antitumorale.
L'utilizzo clinico della CPT è ostacolato sia dalla sua scarsissima idrosolubilità, sia perchè la sua forma attiva lattonica “chiusa” è rapidamente convertita, in condizioni fisiologiche, nella forma carbossilica “aperta”, che è inattiva e si lega in elevata percentuale all'albumina serica.
Attualmente solo due derivati semisintetici della CPT (Topotecan ed Irinotecan) sono utilizzati nella pratica clinica per il trattamento di cancro ovarico, polmonare e colo-rettale.
La recente risoluzione, mediante cristallografia a raggi X, della struttura tridimensionale di TopoI in complesso sia con la Camptotecina e il Topotecan che con derivati strutturalmente diversi (indolocarbazolici ed isochinolinici), ha fornito chiarimenti sulle caratteristiche dell'interazione enzima-inibitore. Tali informazioni costituiscono elementi molto utili nello studio dei veleni di TopoI con un approccio di tipo computazionale il cui scopo è comprendere in che modo queste molecole interagiscono con il loro target e progettare nuovi nuovi derivati come potenziali farmaci ad attività antitumorale. È stato quindi possibile individuare un nuovo farmacoforo sfruttando le cinque strutture cristallogra che disponibili, al fine di rintracciare un set di caratteristiche strutturali comuni a tutti i veleni di TopoI.
Con lo scopo di disporre di nuovi derivati più semplici da ottenere dal punto di vista della sintesi ma che mantengano tutte le caratteristiche farmacoforiche richieste per la formazione di complessi ternari stabili con TopoI e DNA, è stata proposta la sintesi di analoghi “semplificati” della CPT. Si può infatti ipotizzare che una molecola non debba necessariamente possedere uno scaffold
pentaciclico per legarsi al complesso binario TopoI-DNA, purchè mantenga un sistema planare aromatico per intercalare il DNA e opportuni gruppi funzionali in grado di interagire con specifici aminoacidi dell'enzima. Sulla base di questa assunzione, diversi possibili scaffold sono stati disegnati e sottoposti a studi di docking con diversi protocolli di ricerca per predire la loro capacità di formare stabili complessi ternari con TopoI e DNA.
È stato inoltre condotto uno studio di docking molecolare per una serie di nuovi derivati della CPT sostituiti in posizione 5 (5-derivati) per descrivere la loro modalità di interazione con il complesso TopoI-DNA. In generale, l'introduzione di sostituenti in posizione 5 ha come risultato una diminuzione dell'attività citotossica rispetto alla CPT. La presenza di sostituenti lipofili di piccole dimensioni sembra essere tollerata all'interno del sito di binding, mentre l'introduzione di gruppi idro lici dà luogo ad una diminuzione dell'affinità. L'introduzione di gruppi stericamente ingombranti provoca la perdita di importanti interazioni al'interno del sito di legame. I risultati computazionali indicano come caratteristica generale che l'epimero ? dei 5-derivati ha un'affinità maggiore per il sito di binding rispetto all'epimero ?.
Recentemente sono stati sintetizzati una serie di 16a-tio-CPT analoghi. I saggi biologici condotti su questi composti hanno rivelato che i tio-derivati sono potenti inibitori della TopoI ed hanno attività antitumorale maggiore rispetto ai loro oxo-analoghi, sia in vitro che in vivo. Al fine di razionalizzare la maggiore attività dei tio-analoghi rispetto ai derivati tradizionali, è stato eseguito
uno studio computazionale volto sia a predire proprietá chimico-fisiche rilevanti per la descrizione del possibile profilo farmacocinetico delle nuove molecole, sia a descriverne la modalità di legame
nel sito del complesso binario TopoI-DNA tramite studi di docking.
I risultati di docking non hanno messo in evidenza differenze di rilievo tra i tio- e gli oxo-derivati in termini di modalità di binding e di docking score. Al contrario, i valori predetti per proprietà come la lipofilicità, la solubilità in acqua e la permeabilità cellulare indicano che il profilo farmacocinetico delle due classi di composti potrebbe essere significativamente diverso.
Per le simulazioni di docking condotte sui 5-CPT-derivati e sui tio-CPT-derivati è stato utilizzato il protocollo quantum mechanics (QM)-polarized ligand docking (QPLD) (implementato nella suite Schrödinger) con lo scopo di aumentare l'accuratezza dei calcoli di docking. I metodi tradizionali utilizzati per il docking molecolare utilizzano una rappresentazione chimico-fisica approssimata delle interazioni proteina-ligando, dove le cariche atomiche sono calcolate in base al campo di forza. Il protocollo QPLD utilizza invece una metodologia ab initio per il calcolo delle cariche del ligando all'interno della cavità della proteina, tenendo in considerazione la polarizzazione di carica indotta dagli aminoacidi del sito di legame sul ligando.
Il lavoro relativo ai 5-CPT-derivati e ai tio-CPT-derivati à stato supportato dall'azienda farmaceutica Indena S.p.A., Milano, Italia. Il lavoro è stato condotto in collaborazione con il gruppo del Professor Arturo Battaglia (Centro Nazionale Richerche Bologna) per la sintesi dei composti e con il gruppo del Professor Franco Zunino (Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano) per i saggi biologici.

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EPrint type:Ph.D. thesis
Tutor:Moro, Stefano
Ph.D. course:Ciclo 21 > Scuole per il 21simo ciclo > SCIENZE MOLECOLARI > SCIENZE FARMACEUTICHE
Data di deposito della tesi:30 January 2009
Anno di Pubblicazione:January 2009
Key Words:topoisomerase I, camptothecin, DNA, molecular mechanics, molecular docking, QM-polarized ligand docking, 5-substituted camptothecin derivatives, thio-camptothecin derivatives
Settori scientifico-disciplinari MIUR:Area 03 - Scienze chimiche > CHIM/08 Chimica farmaceutica
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Scienze Farmaceutiche
Codice ID:1782
Depositato il:30 Jan 2009
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