Anthropogenic reaction parameters - the missing link between chemical intuition and the available chemical space

How do skilled synthetic chemists develop such a good intuitive expertise ? Why can we only access such a small amount of the available chemical space — both in terms of the re actions used and the chemical scaffolds we make? We argue here that these seemingly unrelated questions have a common root and are strongly interdependent . We performed a comprehensive analysis of organic reaction parameters dating back to 1771 and discove red that there are several anthropogenic factors that limit the reaction parameters and thus the scop e of synthetic chemistry. Nevertheless, many of the anthropogenic limitations such as the narrow parameter space and the opportunity of the rapid and clear feedback on the progress of reactions appear to be crucial for the acquisition of valid and reliable chemical intuition. In parallel, however, all of these same factors represent limitations for the exploration of available chemistry space and we argue th at these are thus at least partly responsible for limited access to new chemistries. We advocate, therefore, that the present anthropogenic boundaries can be expanded by a more conscious expl oration of “off - road” chemistry that would also extend the intuit ive knowledge of trained chemists

Molecular Docking and Biophysical Studies for Antiproliferative Assessment of Synthetic Pyrazolopyrimidinones Tethered with Hydrazide-Hydrazones.

Chemotherapy represents the most applied approach to cancer treatment. Owing to the frequent onset of chemoresistance and tumor relapses, there is an urgent need to discover novel and more effective anticancer drugs. In the search for therapeutic alternatives to treat the cancer disease, a series of hybrid pyrazolo[3,4-d]pyrimidin-4(5H)-ones tethered with hydrazide-hydrazones, 5a–h, was synthesized from condensation reaction of pyrazolopyrimidinone-hydrazide 4 with a series of arylaldehydes in ethanol, in acid catalysis. In vitro assessment of antiproliferative effects against MCF-7 breast cancer cells, unveiled that 5a, 5e, 5g, and 5h were the most effective compounds of the series and exerted their cytotoxic activity through apoptosis induction and G0/G1 phase cell-cycle arrest. To explore their mechanism at a molecular level, 5a, 5e, 5g, and 5h were evaluated for their binding interactions with two well-known anticancer targets, namely the epidermal growth factor receptor (EGFR) and the G-quadruplex DNA structures. Molecular docking simulations highlighted high binding affinity of 5a, 5e, 5g, and 5h towards EGFR. Circular dichroism (CD) experiments suggested 5a as a stabilizer agent of the G-quadruplex from the Kirsten ras (KRAS) oncogene promoter. In the light of these findings, we propose the pyrazolo-pyrimidinone scaffold bearing a hydrazide-hydrazone moiety as a lead skeleton for designing novel anticancer compound

Natural Products-Based Drug Design against SARS-CoV-2 Mpro 3CLpro

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has received global attention due to the serious threat it poses to public health. Since the outbreak in December 2019, millions of people have been affected and its rapid global spread has led to an upsurge in the search for treatment. To discover hit compounds that can be used alone or in combination with repositioned drugs, we first analyzed the pharmacokinetic and toxicological properties of natural products from Brazil’s semiarid region. After, we analyzed the site prediction and druggability of the SARS-CoV-2 main protease (Mpro), followed by docking and molecular dynamics simulation. The best SARS-CoV-2 Mpro complexes revealed that other sites were accessed, confirming that our approach could be employed as a suitable starting protocol for ligand prioritization, reinforcing the importance of catalytic cysteine-histidine residues and providing new structural data that could increase the antiviral development mainly against SARSCoV-2. Here, we selected 10 molecules that could be in vitro assayed in response to COVID-19. Two compounds (b01 and b02) suggest a better potential for interaction with SARS-CoV-2 Mpro and could be further studied.Research Dean and Graduate Studies of the Federal University of Pará (PROPESP/UFPA)Brazilian National Council for Scientific and Technological Development (CNPq)Brazilian Coordination for Improvement of Personnel Higher Education (CAPES)Bahia Research Foundation (FAPESB, grant numbers APP071/2011, JCB-0039/2013, and RED-008/2013

Systematic Identification of Scaffolds Representing Different Types of Structure-Activity Relationships

In medicinal chemistry, it is of central importance to understand structure-activity relationships (SARs) of small bioactive compounds. Typically, SARs are analyzed on a case-by-case basis for sets of compounds active against a given target. However, the increasing amount of compound activity data that is becoming available allows SARs to be explored on a large-scale. Moreover, molecular scaffolds derived from bioactive compounds are also of high interest for SAR analysis. In general, scaffolds are obtained by removing all substituents from rings and from linkers between rings. This thesis aims at systematically mining compounds for which activity annotations are available and investigating relationships between chemical structure and biological activities at the level of active compounds, in particular, molecular scaffolds. Therefore, data mining approaches are designed to identify scaffolds with different structural and/or activity characteristics. Initially, scaffold distributions in compounds at different stages of pharmaceutical development are analyzed. Sets of scaffolds that overlap between different stages or preferentially occur at certain stages are identified. Furthermore, a systematic selectivity profile analysis of public domain active compounds is carried out. Scaffolds that yield compounds selective for communities of closely related targets and represent compounds selective only for one particular target over others are identified. In addition, the degree of promiscuity of scaffolds is thoroughly examined. Eighty-three scaffolds covering 33 chemotypes correspond to compounds active against at least three different target families and thus are considered to be promiscuous. Moreover, by integrating pairwise scaffold similarity and compound potency differences, the propensity of scaffolds to form multi-target activity or selectivity cliffs and, in addition, the global scaffold potential of individual targets are quantitatively assessed, respectively. Finally, structural relationships between scaffolds are systematically explored. Most scaffolds extracted from active compounds are found to be involved in substructure relationships and/or share topological features with others. These substructure relationships are also compared to, and combined with, hierarchical substructure relationships to facilitate activity prediction

Phosphino-Triazole Ligands for Palladium-Catalyzed Cross-Coupling

Twelve 1,5-disubtituted and fourteen 5-substituted 1,2,3-triazole derivatives bearing diaryl or dialkyl phosphines at the 5-position were synthesized and used as ligands for palladium-catalyzed Suzuki–Miyaura cross-coupling reactions. Bulky substrates were tested, and lead-like product formation was demonstrated. The online tool SambVca2.0 was used to assess steric parameters of ligands and preliminary buried volume determination using XRD-obtained data in a small number of cases proved to be informative. Two modeling approaches were compared for the determination of the buried volume of ligands where XRD data was not available. An approach with imposed steric restrictions was found to be superior in leading to buried volume determinations that closely correlate with observed reaction conversions. The online tool LLAMA was used to determine lead-likeness of potential Suzuki–Miyaura cross-coupling products, from which 10 of the most lead-like were successfully synthesized. Thus, confirming these readily accessible triazole-containing phosphines as highly suitable ligands for reaction screening and optimization in drug discovery campaigns

Discovery and development of novel inhibitors for the kinase Pim-1 and G-Protein Coupled Receptor Smoothened

Investigation of the cause of disease is no easy business. This is particularly so when one reflects upon the lessons taught us in antiquity. Prior to the beginning of the last century, diagnosis and treatment of diseases such as cancers was so bereft of hope that there was little physicians could offer in the way of comfort, let alone treatment. One of the major insights from investigations into cancers this century has been that those involved in research leading to treatments are not dealing with a singular malady but multiple families of diseases with different mechanisms and modes of action. Therefore, despite the end game being similar in cancers, that of uncontrolled growth and replication leading to cellular dysfunction, different diseases require different approaches in targeting them. This leads us to a particular broad treatment approach, that of drug design. A drug is, in the classical sense, a small molecule that, upon introduction into the body, interacts with biochemical targets to induce a wider biological effect, ideally with both an intended target and intended effect. The conceptual basis underpinning this `lock-and-key' paradigm was elucidated over a century ago and the primary occupation of those involved in biochemical research has been to determine as much information as possible about both of these protein locks and drug keys. And, as inferred from the paradigm, molecular shape is all-important in determining and controlling action against the most important locks with the most potent and specific keys. The two most important target classes in drug discovery for some time have been protein kinases and G Protein-Coupled Receptors (GPCRs). Both classes of proteins are large families that perform very different tasks within the body. Kinases activate and inactive many cellular processes by catalysing the transfer of a phosphate group from Adenosine Tri-Phosphate (ATP) to other targets. GPCRs perform the job of interacting with chemical signals and communicating them into a biological response. Dysfunction in both types of proteins in certain cells can lead to a loss of biological control and, ultimately, a cancer. Both of kinases and GPCRs have entirely different chemical structures so structural knowledge therefore becomes crucial in any approach targeting cells where dysfunction has occurred. Thus, for this thesis, a member from each class was investigated using a combination of structural approaches. From the kinase class, the kinase Proviral Integration site for MuLV (Pim-1) and from the GPCR class, the cell membrane-bound Smoothened receptor (SMO). The kinase \pimone\ was the target of various approaches in \autoref{chap:three}. Although a heavily studied target from the mid-2000's, there is a paucity of inhibitors targeting residues more remote from structural characteristics that define kinases. Further limiting extension possibilities is that \pimone\ is constitutively active so no inhibitors targeting an inactive state are possible. An initial project (\pone) used the known binding properties of small molecules, or, `fragments' to elucidate structural and dynamic information useful for targeting \pimone. This was followed by three projects, all with the goal of inhibitor discovery, all with different foci. In \ptwo, fragment binding modes from \pone\ provided the basis for the extension and development of drug-like inhibitors with a focus on synthetic feasibility. In contrast, inhibitors were found in \pthree\ via a large-scale public dataset of purchasable molecules that possess drug-like properties. Finally, \pfour\ took the truncated form of a particularly attractive fragment from \pone\ that was crystallised with \pimone, verified its binding mode and then generated extensions with, again, a focus on synthetic feasibility. The GPCR \smo\ has fewer molecular studies and much about its structural behaviour remains unknown. As the most `druggable' protein in the Hedgehog pathway, structural studies have primarily focussed on stabilising its inactive state to prevent signal transduction. Allied to this is that there are generally few inhibitors for \smo\ and the drugs for cancers related to its dysfunction are vulnerable to mutations that significantly reduce their effectiveness or abrogate it entirely. The elucidation of structural information in therefore of high priority. An initial study attempting to identify an unknown molecule from prior experiments led to insights regarding binding characteristics of specific moieties. This was particularly important to understand not just where favourable moieties bind but also sections of the \smo\ binding pocket with unfavourable binding. In both subsequent virtual screens performed in Chapter 4, the primary aim was to find new drug-like inhibitors of \smo\ using large public datasets of commercially-available molecules. The initial screen retrieved relatively few inhibitors so the binding pocket was modified to find a structural state more amenable to small molecule binding. These modifications led to a significant number of new, chemically novel inhibitors for \smo, some structural information useful for future inhibitors and the elucidation of structure-activity relationships useful for inhibitor design. This underpins the idea that structural information is of critical importance in the discovery and design of molecular inhibitors

Biointormatics of Targeted Therapeutics And Applications in Drug Discovery

Ph.DDOCTOR OF PHILOSOPH

Bioinformatics Analysis and Modelling of Therapeutically Relevant Molecules

Ph.DDOCTOR OF PHILOSOPH

Sondas fotoquímicas y materiales luminiscentes para la detección de micotoxinas carboxiladas

En los últimos años la seguridad alimentaria se ha convertido en una preocupación creciente, no sólo para los poderes públicos y productores del sector alimentario, sino también para el conjunto de la sociedad. Entre los contaminantes químicos de los alimentos considerados como peligrosos se incluyen algunos tipos de micotoxinas. Pese a la gran diversidad química estructural que presenta este tipo de compuestos, las micotoxinas son productos naturales, generados como metabolitos secundarios por hongos filamentosos, cuyo peso molecular se encuentra alrededor de los 700 g/mol. Son altamente ionizables y, por ello, muy reactivos; al reaccionar con distintas dianas de las células eucariotas dan lugar a efectos nocivos para la salud humana, influyendo en la tasa creciente de enfermedades crónicas como infertilidad, defectos de nacimiento, deterioro del sistema inmunológico, lesiones cerebrales, etc. Paralelamente a la preocupación por la toxicidad en los alimentos, las técnicas analíticas han experimentado un gran avance y, con ellas, la tecnología de sensores químicos está alcanzando un extraordinario grado de sofisticación como alternativa a los métodos cromatográficos que requieren grandes y costosos equipos, así como personal especializado. Con el fin de desarrollar nuevos sensores químicos con la sensibilidad y selectividad necesarias para la determinación de micotoxinas en alimentos, se plantea la presente Tesis, la cual trata de combinar por un lado el campo de los polímeros con impronta molecular (MIPs) y, por otro, el de los polímeros conjugados luminiscentes (CLPs)..