Tse, Ching Man. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (p. 188-200). / Abstracts in English and Chinese. / Abstract --- p.i / Acknowledgement --- p.vi / Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Obtain information on drug targets --- p.3 / Chapter 1.2 --- Drug Design --- p.5 / Chapter 1.3 --- Interface for interaction --- p.9 / Chapter 1.4 --- Summary --- p.10 / Chapter 2 --- Background Study --- p.12 / Chapter 2.1 --- Protein Function Prediction --- p.16 / Chapter 2.2 --- Drug Design --- p.37 / Chapter 2.3 --- Visualisation and Interaction in Biomedic --- p.44 / Chapter 3 --- Overview --- p.48 / Chapter 3.1 --- Protein prediction using secondary structure analysis --- p.52 / Chapter 3.2 --- Knowledge-driven ligand design --- p.55 / Chapter 3.3 --- Interactive interface in virtual reality --- p.57 / Chapter 4 --- Protein Function Prediction --- p.60 / Chapter 4.1 --- Introduction --- p.61 / Chapter 4.1.1 --- Motivation --- p.61 / Chapter 4.1.2 --- Objective --- p.62 / Chapter 4.1.3 --- Overview --- p.63 / Chapter 4.2 --- Methods and Design --- p.66 / Chapter 4.2.1 --- Feature Cell --- p.68 / Chapter 4.2.2 --- Heterogeneous Vector --- p.71 / Chapter 4.2.3 --- Feature Cell Similarity --- p.75 / Chapter 4.2.4 --- Heterogeneous Vector Similarity --- p.79 / Chapter 4.3 --- Experiments --- p.85 / Chapter 4.3.1 --- Data Preparation --- p.85 / Chapter 4.3.2 --- Experimental Methods --- p.87 / Chapter 4.4 --- Results --- p.97 / Chapter 4.4.1 --- Scalability --- p.97 / Chapter 4.4.2 --- Cluster Quality --- p.99 / Chapter 4.4.3 --- Classification Quality --- p.102 / Chapter 4.5 --- Discussion --- p.103 / Chapter 4.6 --- Conclusion --- p.104 / Chapter 5 --- Drug Design --- p.106 / Chapter 5.1 --- Introduction --- p.107 / Chapter 5.1.1 --- Motivation --- p.107 / Chapter 5.1.2 --- Objective --- p.109 / Chapter 5.1.3 --- Overview --- p.109 / Chapter 5.2 --- Methods --- p.111 / Chapter 5.2.1 --- Fragment Joining --- p.115 / Chapter 5.2.2 --- Genetic Operators --- p.116 / Chapter 5.2.3 --- Post-Processing --- p.124 / Chapter 5.3 --- Experiments --- p.128 / Chapter 5.3.1 --- Data Preparation --- p.129 / Chapter 5.3.2 --- Experimental Methods --- p.132 / Chapter 5.4 --- Results --- p.134 / Chapter 5.4.1 --- Binding Pose --- p.134 / Chapter 5.4.2 --- Free Energy and Molecular Weight --- p.137 / Chapter 5.4.3 --- Execution Time --- p.138 / Chapter 5.4.4 --- Handling Phosphorus --- p.138 / Chapter 5.5 --- Discussions --- p.139 / Chapter 5.6 --- Conclusion --- p.140 / Chapter 6 --- Interface in Virtual Reality --- p.142 / Chapter 6.1 --- Introduction --- p.143 / Chapter 6.1.1 --- Motivation --- p.143 / Chapter 6.1.2 --- Objective --- p.145 / Chapter 6.1.3 --- Overview --- p.145 / Chapter 6.2 --- Methods and Design --- p.146 / Chapter 6.2.1 --- Hybrid Drug Synthesis --- p.147 / Chapter 6.2.2 --- Interactive Interface in Virtual Reality --- p.154 / Chapter 6.3 --- Experiments and Results --- p.171 / Chapter 6.3.1 --- Data Preparation --- p.171 / Chapter 6.3.2 --- Experimental Settings --- p.172 / Chapter 6.3.3 --- Results --- p.173 / Chapter 6.4 --- Discussions --- p.176 / Chapter 6.5 --- Conclusions --- p.179 / Chapter 7 --- Conclusion --- p.180 / A Glossary --- p.184 / Bibliography --- p.188

Title from title screen. Interactive three dimensional molecular data and multiple colour images. Text presented in Hypertext Markup Language (.htm); images in standard formats (.jpg, .gif); molecules presented mostly as Cambridge Protein Data Bank format (.pdb); some molecules presented in alternative X.Mol cartesian co-ordinates format (.xyz); search facility in PERL script. Includes bibliographical references. Text, numeric and representational data System requirements: for text, any standard web browser on any platform, Netscape 2.x or higher, Internet Explorer 3.x or higher; for molecular structures, viewer such as Rasmol or preferably MDL's Chemscape Chime; for search facility , an appropriately configured web server. Links to all required software for browsing on various platforms are included in the software directory in the thesis. Mode of access: World Wide Web.

In 2015, an estimated 46.8 million people were living with dementia, a number predicted to increase to 74.7 million by 2030 and 131.5 million by 2050. Whilst there are numerous causes for the development of dementia, Alzheimer's disease is by far the most common, accounting for approximately 50-70% of all cases. Current therapeutic agents against Alzheimer's disease are palliative in nature, managing symptoms without addressing the underlying cause and thus disease progression and patient death remain a certainty. Whilst the main underlying cause for the development of Alzheimer's disease was originally thought to be an abnormal deposition of insoluble amyloid-β peptide derived plaques within the brain, the failure of several high-profile therapeutic agents, which were shown to reduce the plaque burden without improving cognition, has recently prompted a shift in focus to soluble oligomeric forms of amyloid-β peptide. Such soluble oligomers have been shown to be toxic in their own right and to precede plaque deposition. Soluble amyloid-β oligomers have been identified in various subcellular compartments, including the mitochondria, where they form a complex with the 17β-HSD10 enzyme resulting in cytotoxicity. Interestingly, hallmarks of this toxicity have been shown to be dependent on the catalytic activity of the 17β-HSD10 enzyme, suggesting two therapeutic approaches may hold merit in treating Alzheimer's disease: disrupting the interaction between the 17β-HSD10 enzyme and amyloid-β peptide, or directly inhibiting the catalytic activity of the 17β-HSD10 enzyme. In 2006, Frentizole was identified as a small molecule capable of disrupting the 17β-HSD10/amyloid interaction. The work described herein details the generation of a robust screening assay allowing the catalytic activity of the 17β-HSD10 enzyme to be measured in vitro. This assay was subsequently employed for small molecule screening using two methodologies; first in a targeted approach using compounds derived from the Frentizole core scaffold, and second in an explorative manner using a diverse library of compounds supplied by the National Cancer Institute. As a result, a range of novel small molecule inhibitors of the 17β-HSD10 enzyme have been identified and the most promising characterised in terms of potency and mechanism of action. De-selection assays were developed to allow the efficient triage of hit compounds and work was begun on a cellular based assay which would allow the ability of compounds of interest to reverse a disease relevant phenotype to be assessed in a cellular environment. As such, we now have a number of hit compounds which will form the basis for the generation of subsequent series of derivatives with improved potency and specificity, as well as the robust assays required to measure such criteria, potentially leading to the generation of novel therapeutic agents against Alzheimer's disease.

A series of 3-aminotetralins were synthesized as potential opioid antagonists. Each proposed target compound was based on a 3-(mono- or dialkylamino )-7 -(hydroxy or methoxy)-2, 2-dimethyl-1-tetralone parent structure. Three synthetic schemes were developed utilizing the common intermediate, ethyl3-benzylamino-2, 2-dimethyl-4-(4- methoxyphenyl)butyrate 3. In Scheme I, compound 3 was modified through a series of six steps to obtain 3-(N-methyl-N-cyclopropanecarboxamido )-7 -methoxy-2, 2-dimethyl- 1-hydroxy-1-phenyltetralin (9). To carry out further synthetic steps on the intermediate 9 required the reduction of the amide function, which proved to be problematic in terms of product isolation. Scheme II was a four-step procedure, which utilized the intermediate ethyl 3- amino-2, 2 dimethyl-4-(4-methoxyphenyl)butyrate (4), also utilized in Scheme I. Ester hydrolysis of the amino ester 4 produced the amino acid 12. Internal cyclization of 12 yielded the key intermediate, 3-amino-7 -methoxy-2, 2-dimethyl-1-tetralone (13). TheNalkylation step was carried out on 13 and this yielded the target compounds, 3-[N- ( cyclopropylmethyl)amino ]- and 3-[N, N-( dicyclopropylmethyl)amino ]-7 -methoxy-2, 2- dimethyl-1-tetralone (14, 15). Subsequently, compounds 14 and 15 were 0-demethylated to obtain the respective target compounds, 3-[N-(cyclopropylmethyl)amino]- and 3-[N, N-(dicyclopropylmethyl)amino ]-7-hydroxy-2, 2-dimethyl-1-tetralone (16, 17). Scheme III was an alternate synthetic route to obtain the target compounds 3-[Nmethyl- N-( cyclopropylmethyl)amino ]-2, 2-dimethyl-7-(hydroxy or methoxy)-1-hydroxy- 1-phenyltetralin (10, 11) without the amide reduction step required in Scheme I. The intermediate 3 was N-methylated to form the 3-N-methyl-N-benzylamino ester 18 by the Eschweiler-Clarke procedure. Compound 18 was converted through a series of four steps to obtain 3-[ N-methyl-N-( cyclopropylmethyl)amino ]-7 -methoxy-2, 2-dimethyl-1- tetralone (22), a target compound which was 0-demethylated to obtain compound 23, the 7-0H analog. The mono- and dialkylated 3-aminotetralins were synthesized and confirmed for purity and correct molecular formula by utilizing 1H NMR, 13C NMR, mass spectrometry, and elemental analysis. The target compounds 14, 15, 16, 17,22 and 23 were converted to their salts and are being analyzed for opioid-related activity in receptor binding assays.

With antimicrobial resistance to current drugs steadily rising, the development of new antibiotics with novel mechanisms of action has become an imperative. The majority of life-threatening infections worldwide are caused by "ESKAPE" pathogens which are encountered in more than 40% of hospital-acquired infections, and are resistant to the majority of commonly used antibiotics. Naturally occurring cyclic depsipeptides, microbial secondary metabolites that contain one or more ester bonds in addition to amide bonds, have emerged as an important source of pharmacologically active compounds or lead structures for the development of novel antibiotics. Some of those peptides are either already marketed (daptomycin) or in advanced stages of clinical development (ramoplanin). Structurally simple, yet potent, fusaricidin/LI-F and lysobactin families of naturally occurring antibiotics represent particularly attractive candidates for the development of new antibacterial agents capable of overco ming infections caused by multidrug-resistant bacteria. These natural products exhibit potent antimicrobial activity against a variety of clinically relevant fungi and Gram-positive bacteria. Therefore, access to these classes of natural products and their synthetic analogs, combined with elucidation of their mode of action represent important initial steps toward full exploitation of their antmicrobial potential. This dissertation describes a general approach toward the solid-phase synthesis of fusaricidin/LI-F and lysobactin analogs and an extensive structure-activity relationship (SAR) study. We have devised a simple and robust preparation strategy based on standard Fmoc solid-phase peptide synthesis protocols. / The SAR study revealed key structural requirements for fusaricidin/LI-F and related cyclic lipopeptides antibacterial activity, including the presence of the guanidino moietly at the end of the lipidic tail, hydrophobic amino acid residues, and peptide conformation Moreover, substitution of the ester bond with an amide bond significantly improved stability under physiologically relevant conditions and reduced toxicity. In addition, we have shown that these antibacterial peptides exert their mode of action via a novel mechanism, which invloves bacterial membrane interactions, followed by peptide internalization. Altogether, the research described in this dissertation demonstrates that new antibiotics derived from fusaricidin/LI-F natural products, have the potential to meet the challenge of antibiotic resistance in Gram-positive bacteria. / by Nina Bionda. / Thesis (Ph.D.)--Florida Atlantic University, 2013. / Includes bibliography. / Mode of access: World Wide Web. / System requirements: Adobe Reader.

Nucleic acids have proven to be viable targets for small molecule drugs. While many examples of such drugs are detailed in the literature, only a select few have found practical use in a clinical setting. These currently employed nucleic acid targeting therapies suffer from either debilitating off-target side effects or succumb to a resistance mechanism of the target. The need for new small molecules that target nucleic acids is evident. However, designing a novel drug to bind to DNA or RNA requires a detailed understanding of exactly what binding environments each nucleic acid presents. In an effort to broaden this knowledge, the work presented in this thesis details the binding location and affinity of known and novel nucleic acid binding small molecules with targets ranging from simple RNA secondary structure all the way to the complex structure of ribosomal RNA. Specifically, it is shown that the anthracycline class of antineoplastics prefer to bind at or near mismatch base pairs in both physiologically relevant iron responsive element RNA hairpin constructs as well as DNA hairpin constructs presenting mismatched base pairs. Also characterized in this thesis is a novel class of topoisomerase II / histone deacetylase inhibitor conjugates that display a unique affinity for DNA over RNA. Finally, the novel class of macrolide-peptide conjugates, known as peptolides, are shown to retain potent translation inhibition of the prokaryotic ribosome. The binding pocket of the peptolides, including a crevice previously unreachable by macrolides that extends away from the peptidyl transferase center toward the subunit interface, is confirmed in detail via chemical footprinting of the 70S ribosome. Overall, the identification of a novel binding site for the anthracycline class of drugs and the characterization of the two novel drug designs presented in this thesis will undoubtedly aid in the effort to design and discover new molecules that aim for nucleic acid targets. For example, the anthracycline derivative topoisomerase II / histone deacetylase inhibitor conjugates, with their differential mode of nucleic acid binding, may prove to have a unique side effect profile in a therapeutic application. The peptolide compounds also have the potential to be applied as novel antibiotics as they bind to an area of the prokaryotic ribosome unrelated to known macrolide resistance mutations. Furthermore, as a result of the observation of this thesis work that some peptolides also posses eukaryotic translation inhibition capabilities, they could prove to be useful in preventing the growth of rapidly proliferating eukaryotic cells such as plasmodium, leishmania, or tumor cells. Additionally, different head groups could be utilized in creating new peptolides; for example, an oxazolidinone antibiotic could be employed to sample a different binding area of the ribosome.

Tracking the evolution of function in enzyme superfamilies is key in understanding how important biological functions and mechanisms have evolved. New genes are being sequenced at a rate that far surpasses the ability of characterization by wet-lab techniques. Moreover, bioinformatics allows for the use of methods not amenable to wet lab experimentation. We now face a situation in which we are aware of the existence of many gene families but are ignorant of what they do and how they function. Even for families with many structurally and functionally characterized members, the prediction of function of ancestral sequences can be used to elucidate past patterns of evolution and highlight likely future trajectories. In this thesis, we apply in silico structure and function methods to predict the functions of protein sequences from two diverse superfamily case studies. In the first, the metallo-β-lactamase superfamily, many members have been structurally and functionally characterised. In this work, we asked how many times the same function has independently evolved in the same superfamily using ancestral sequence reconstruction, homology modelling and alignment to catalytic templates. We found that in only 5% of evolutionary scenarios assessed, was there evidence of a lactam hydrolysing ancestor. This could be taken as strong evidence that metallo-β-lactamase function has evolved independently on multiple occasions. This finding has important implications for predicting the evolution of antibiotic resistance in this protein fold. However, as discussed, the interpretation of this statistic is not clear-cut. In the second case study, we analysed protein sequences of the DUF-62 superfamily. In contrast to the metallo-β-lactmase superfamily, very few members of this superfamily have been structurally and functionally characterised. We used the analysis of alignment, gene context, species tree reconciliation and comparison of the rates of evolution to ask if other functions or cellular roles might exist in this family other than the ones already established. We find that multiple lines of evidence present a compelling case for the evolution of different functions within the Archaea, and propose possible cellular interactions and roles for members of this enzyme family.

Quality by Design (QbD) is a systematic approach that has been recommended as suitable for the development of quality pharmaceutical products. The QbD approach commences with the definition of a quality target drug profile and predetermined objectives that are then used to direct the formulation development process with an emphasis on understanding the pharmaceutical science and manufacturing principles that apply to a product. The design space is directly linked to the use of QbD for formulation development and is a multidimensional combination and interaction of input variables and process parameters that have been demonstrated to provide an assurance of quality. The objective of these studies was to apply the principles of QbD as a framework for the optimisation of a sustained release (SR) formulation of salbutamol sulphate (SBS), and for the establishment of a design space using Response Surface Methodology (RSM) and Artificial Neural Networks (ANN). SBS is a short-acting ♭₂ agonist that is used for the management of asthma and chronic obstructive pulmonary disease (COPD). The use of a SR formulation of SBS may provide clinical benefits in the management of these respiratory disorders. Ashtalin®8 ER (Cipla Ltd., Mumbai, Maharashtra, India) was selected as a reference formulation for use in these studies. An Ishikawa or Cause and Effect diagram was used to determine the impact of formulation and process factors that have the potential to affect product quality. Key areas of concern that must be monitored include the raw materials, the manufacturing equipment and processes, and the analytical and assessment methods employed. The conditions in the laboratory and manufacturing processes were carefully monitored and recorded for any deviation from protocol, and equipment for assessment of dosage form performance, including dissolution equipment, balances and hardness testers, underwent regular maintenance. Preliminary studies to assess the potential utility of Methocel® Kl OOM, alone and in combination with other matrix forming polymers, revealed that the combination of this polymer with xanthan gum and Carbopol® has the potential to modulate the release of SBS at a specific rate, for a period of 12 hr. A central composite design using Methocel® KlOOM, xanthan gum, Carbopol® 974P and Surelease® as the granulating fluid was constructed to fully evaluate the impact of these formulation variables on the rate and extent of SBS release from manufactured formulations. The results revealed that although Methocel® KlOOM and xanthan gum had the greatest retardant effect on drug release, interactions between the polymers used in the study were also important determinants of the measureable responses. An ANN model was trained for optimisation using the data generated from a central composite study. The efficiency of the network was optimised by assessing the impact of the number of nodes in the hidden layer using a three layer Multi Layer Perceptron (MLP). The results revealed that a network with nine nodes in the hidden layer had the best predictive ability, suitable for application to formulation optimisation studies. Pharmaceutical optimisation was conducted using both the RSM and the trained ANN models. The results from the two optimisation procedures yielded two different formulation compositions that were subjected to in vitro dissolution testing using USP Apparatus 3. The results revealed that, although the formulation compositions that were derived from the optimisation procedures were different, both solutions gave reproducible results for which the dissolution profiles were indeed similar to that of the reference formulation. RSM and ANN were further investigated as possible means of establishing a design space for formulation compositions that would result in dosage forms that have similar in vitro release test profiles comparable to the reference product. Constraint plots were used to determine the bounds of the formulation variables that would result in the manufacture of dosage forms with the desired release profile. ANN simulations with hypothetical formulations that were generated within a small region of the experimental domain were investigated as a means of understanding the impact of varying the composition of the formulation on resultant dissolution profiles. Although both methods were suitable for the establishment of a design space, the use of ANN may be better suited for this purpose because of the manner in which ANN handles data. As more information about the behaviour of a formulation and its processes is generated during the product Iifecycle, ANN may be used to evaluate the impact of formulation and process variables on measureable responses. It is recommended that ANN may be suitable for the optimisation of pharmaceutical formulations and establishment of a design space in line with ICH Pharmaceutical Development [1], Quality Risk Management [2] and Pharmaceutical Quality Systems [3]

Con el fin de relacionar la estructura y la actividad de series de compuestos, es importante usar descriptores moleculares relevantes. Los descriptores GRIND y VolSurf pertenecen a una nueva familia de descriptores llamado libre de alineamiento. Es decir, que no necesitan alinear los compuestos con el fin de comparar sus campos de interacciones molecular. En este estudio se ha aplicado esos descriptores para la selección de reactivos químicos a partir de una amplia base de datos. La selección se ha echo mediante un protocolo que permite maximizar la diversidad de la muestra y así obtener unos compuestos muy informativos. También se ha desarrollado nuevos descriptores de forma que están basado en los cambios de curvatura de la superficie molecular. Los resultados obtenidos indican que los nuevos descriptores de forma se integran muy bien en los descriptores GRIND originales y que permiten identificar los efectos de forma tanto favorable como desfavorable. Además, se ha desarrollado nuevos descriptores libre de alineamiento llamado 'anchor-GRIND' que usan un átomo de cada molécula como punto de referencia para la comparación de los campos de interacciones molecular. Los descriptores 'anchor-GRIND' permiten una descripción mas precisa y mas sencilla que los descriptores GRIND lo que los hace mas relevante para el análisis de ciertas familias de compuestos. / In order to correlate the differences of structure with the differences of activity of series of compounds, it is important to use relevant molecular descriptors. The GRIND and VolSurf descriptors belong to the so-called alignment-free descriptors family. In other words, they do not require to align the compounds in order to compare its molecular interaction fields. In this study, we applied these descriptors to the selection of chemical reagent from a database of compounds. The selection has been done following a protocol which allows to maximize the diversity of the sample and so to obtain some compounds highly informative. In addition we developed new shape descriptors which are based on the changes of curvature of the molecular surface. The results obtained show that the new shape descriptors are well integrated in the original GRIND descriptors. Furthermore, we designed new alignment-free descriptors called 'anchor-GRIND' which use one atom of each molecule as a reference point for the comparison of the molecular interaction fields. The 'anchor-GRIND' descriptors allow a more precise and more simple description than the GRIND descriptors, which makes them more relevant for the analysis of some families of compounds.

La medicina personalitzada i les teràpies dirigides són, avui dia, estratègies emergents en les companyies farmacèutiques. L’objectiu global, a llarg termini, és desenvolupar tractaments dirigits cap a mecanismes moleculars desregulats únicament en les cèl•lules afectades, reduint així els problemes de toxicitat d’aquests compostos. Aquest procés és llarg i costós però la introducció de les tècniques de disseny racional de fàrmacs ha permès reduir de manera considerable el temps d’identificació de molècules actives, agilitzant així les etapes inicials. Les teràpies antitumorals dirigides a promoure l’apoptosi i/o a controlar el procés de proliferació cel•lular es troben avui dia en ple desenvolupament. A més, les oportunitats d’intervenció terapèutiques en aquesta línia s’incrementen a mesura que augmenta el coneixement de les proteïnes involucrades en aquests processos. Avui dia els principals problemes dels compostos identificats radiquen però en la seva selectivitat i el gran nombre d’efectes secundaris que presenten, pel que el disseny del molècules selectives és un camp de recerca molt actiu. El present projecte es basa en la cerca de nous fàrmacs anticancerígens mitjançant la modelització molecular. D’una banda es tracta d’identificar inhibidors per a les proteïnes de la família Bcl-2 per a restablir els nivells normals d’apoptosi i, de l’altra, per a les proteïnes CDK4 i CDK6, importants reguladores del cicle cel•lular. L’objectiu plantejat a llarg termini en aquesta tesi és identificar compostos actius amb potència i selectivitat cap a aquestes proteïnes per tal de convertir-los en caps de sèrie que finalment puguin arribar a ser fàrmacs comercials. La utilització de compostos mimètics del domini BH3 per inhibir la funció dels membres antiapoptòtics de la família Bcl-2 és una de les estratègies més emprades per al control de l’apoptosi. En aquest marc, en funció de la selectivitat que presenten envers els pèptids BH3, podem trobar dues subfamílies de proteïnes antiapoptòtiques: Bcl-2, Bcl-xL i Bcl-w d’una banda i Mcl-1 i A-1 de l’altra. Diferents estudis suggereixen que per a produir la mort cel•lular és necessari intervenir al menys un membre de cadascuna de les subfamílies. Per tant, sota aquesta premissa, es van analitzar les interaccions establertes entre les proteïnes antiapoptòtiques i dominis BH3 tant pel cas de pèptids que s’uneixen amb igual afinitat a tota la família, com per a pèptids selectius de cadascun dels subgrups. Nombrosos estudis apunten a que la helicitat en els pèptids mimètics dels domini BH3 incrementa notablement l’afinitat d’enllaç. Sota aquesta premissa s’ha tractat de dissenyar pèptids derivats de la proteïna proapoptòtica Bak substituint alguns dels residus prescindibles per l’aminoàcid no natural Aib, inductor de conformacions helicoïdals. Actualment tots els inhibidors coneguts per a les CDKs, actuen sobre el lloc d’unió de l’ATP. Donat que existeix una gran quantitat de dades experimentals sobre aquests compostos es va decidir avaluar diferents algoritmes de docking i predicció d’afinitats experimentals amb cinc inhibidors coneguts de CDK6. Finalment, s’ha proposat també un desenvolupament metodològic que enfoca el problema del disseny de fàrmacs des d’una perspectiva més amplia: la quimiogenòmica. Amb la seqüenciació del genoma humà s’ha pres consciència de que resulta inviable avaluar el gran número de compostos químics coneguts actualment sobre totes les possibles dianes terapèutiques identificades en el genoma humà. Per aquest motiu és imprescindible desenvolupar mètodes teòrics més senzills per a la caracterització i comparació de molècules que permetin predir la seva activitat biològica. Així doncs, amb la realització d’aquesta tesi, queda patent que l’aplicació de mètodes teòrics pot contribuir de manera eficient al disseny de fàrmacs. D’aquesta manera es possible reduir el cost i temps necessari per al descobriment de compostos actius. / Nowadays, personalized medicine and directed therapies have emerged as appealing strategies for pharmaceutical companies. The long-term goal is developing new treatments to target molecular pathways altered only in affected cells, thus reducing undesired side effects and toxicity problems. This is a tedious and long process although the incorporation in its framework of rational drug design techniques has reduced the time needed to identify new active molecules. The knowledge of molecular mechanisms involved in a given pathology allows finding a point of the process that can be targeted, usually a protein, restoring the normal cell behavior. Once identified the therapeutic target it is possible to find compounds that reproduce interactions between this protein and the corresponding natural regulations by means of molecular modeling techniques. In principle, these compounds are expected to mimic the biological effect of the natural regulators. Antitumoral therapies oriented to promote apopotosis or control the cell proliferation process are gaining importance nowadays. In addition, opportunities for therapeutic intervention in this context are growing with the discovery of new proteins involved in these pathways. In fact, the drawback of compounds known at date relies on selectivity problems and, thus, the huge number of undesired side effects of these treatments. Hence, development of selective treatments is a very active research field. The goal of the present PhD project is to identify new anticancer agents using molecular modeling techniques. On the one hand, it has been tried to identify inhibitors of the Bcl-2 protein family in order to restore normal apoptosis levels in tumoral cells and, on the other hand, for the CDK4 and CDK6 proteins, key regulators of eukaryotic cell cycle. All these proteins are deregulated in many types of cancer and thus, are presented as interesting targets for the cancer treatment. The identification of compounds with potency and selectivity for these proteins that can be used as lead compounds that finally will become commercial drugs is seeked.