From Medicinal Chemistry to Human Health: Current Approaches to Drug Discovery for Cancer and Neglected Tropical Diseases.

Scientific and technological breakthroughs have compelled the current players in drug discovery to increasingly incorporate knowledge-based approaches. This evolving paradigm, which has its roots attached to the recent advances in medicinal chemistry, molecular and structural biology, has unprecedentedly demanded the development of up-to-date computational approaches, such as bio- and chemo-informatics. These tools have been pivotal to catalyzing the ever-increasing amount of data generated by the molecular sciences, and to converting the data into insightful guidelines for use in the research pipeline. As a result, ligand- and structure-based drug design have emerged as key pathways to address the pharmaceutical industry's striking demands for innovation. These approaches depend on a keen integration of experimental and molecular modeling methods to surmount the main challenges faced by drug candidates - in vivo efficacy, pharmacodynamics, metabolism, pharmacokinetics and safety. To that end, the Laboratório de Química Medicinal e Computacional (LQMC) of the Universidade de São Paulo has developed forefront research on highly prevalent and life-threatening neglected tropical diseases and cancer. By taking part in global initiatives for pharmaceutical innovation, the laboratory has contributed to the advance of these critical therapeutic areas through the use of cutting-edge strategies in medicinal chemistry.

[1]  G. Oliva,et al.  Enzyme kinetics, structural analysis and molecular modeling studies on a series of Schistosoma mansoni PNP inhibitors , 2011 .

[2]  Leonardo L. G. Ferreira,et al.  Targeting cysteine proteases in trypanosomatid disease drug discovery , 2017, Pharmacology & therapeutics.

[3]  J. Boissier,et al.  Schistosomiasis chemotherapy. , 2013, Angewandte Chemie.

[4]  Jian Wang,et al.  Whole-genome sequence of Schistosoma haematobium , 2012, Nature Genetics.

[5]  S. Montgomery,et al.  Estimating the Burden of Chagas Disease in the United States , 2016, PLoS neglected tropical diseases.

[6]  J. Dopazo Genomics and transcriptomics in drug discovery. , 2014, Drug discovery today.

[7]  N. Lecland,et al.  The dynamics of microtubule minus ends in the human mitotic spindle , 2014, Nature Cell Biology.

[8]  Girinath G. Pillai,et al.  Quantitative Structure-Activity/Property Relationships: The Ubiquitous Links between Cause and Effect , 2012 .

[9]  Mark McAllister,et al.  Early pharmaceutical profiling to predict oral drug absorption: current status and unmet needs. , 2014, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[10]  Luma G. Magalhães,et al.  Discovery of a Series of Acridinones as Mechanism-Based Tubulin Assembly Inhibitors with Anticancer Activity , 2016, PloS one.

[11]  J. Coura,et al.  Chronic phase of Chagas disease: why should it be treated? A comprehensive review. , 2011, Memorias do Instituto Oswaldo Cruz.

[12]  G. Oliva,et al.  Structural basis for selective inhibition of purine nucleoside phosphorylase from Schistosoma mansoni: kinetic and structural studies. , 2010, Bioorganic & medicinal chemistry.

[13]  Michael J. Keiser,et al.  Complementarity Between a Docking and a High-Throughput Screen in Discovering New Cruzain Inhibitors† , 2010, Journal of medicinal chemistry.

[14]  Luc Kestens,et al.  Human schistosomiasis , 2006, The Lancet.

[15]  Li Di,et al.  Strategic Approaches to Optimizing Peptide ADME Properties , 2014, The AAPS Journal.

[16]  Eiman Mukhtar,et al.  Targeting Microtubules by Natural Agents for Cancer Therapy , 2014, Molecular Cancer Therapeutics.

[17]  T. Blundell,et al.  Structural biology and drug discovery of difficult targets: the limits of ligandability. , 2012, Chemistry & biology.

[18]  Inho Choi,et al.  Computer Aided Drug Design: Success and Limitations. , 2016, Current pharmaceutical design.

[19]  J. Fernández-Recio,et al.  Established and emerging trends in computational drug discovery in the structural genomics era. , 2012, Chemistry & biology.

[20]  C. Twelves,et al.  Tubulin: an example of targeted chemotherapy. , 2013, Future medicinal chemistry.

[21]  M. Vidyavathi,et al.  Role of Human Liver Microsomes in In Vitro Metabolism of Drugs—A Review , 2010, Applied biochemistry and biotechnology.

[22]  Marcelo Santos Castilho,et al.  Discovery of New Inhibitors of Schistosoma mansoni PNP by Pharmacophore-Based Virtual Screening , 2010, J. Chem. Inf. Model..

[23]  Wei Huang,et al.  The Schistosoma japonicum genome reveals features of host–parasite interplay , 2009, Nature.

[24]  A. Andricopulo,et al.  2D Quantitative structure-activity relationship studies on a series of cholesteryl ester transfer protein inhibitors. , 2007, Bioorganic & medicinal chemistry.

[25]  D. Swinney,et al.  How were new medicines discovered? , 2011, Nature Reviews Drug Discovery.

[26]  Leonardo L. G. Ferreira,et al.  Drug repositioning approaches to parasitic diseases: a medicinal chemistry perspective. , 2016, Drug discovery today.

[27]  Adriano D. Andricopulo,et al.  PK/DB: database for pharmacokinetic properties and predictive in silico ADME models , 2008, Bioinform..

[28]  Adriano D Andricopulo,et al.  Development of a natural products database from the biodiversity of Brazil. , 2013, Journal of natural products.

[29]  Donna A Volpe,et al.  Drug-permeability and transporter assays in Caco-2 and MDCK cell lines. , 2011, Future medicinal chemistry.

[30]  C. Wall,et al.  Colchicine toxicity in renal patients - Are we paying attention? , 2016, Clinical nephrology.

[31]  Leonardo L. G. Ferreira,et al.  Molecular Docking and Structure-Based Drug Design Strategies , 2015, Molecules.

[32]  R. S. Ferreira,et al.  Synthesis, biological evaluation, and structure-activity relationships of potent noncovalent and nonpeptidic cruzain inhibitors as anti-Trypanosoma cruzi agents. , 2014, Journal of medicinal chemistry.

[33]  Leonardo L. G. Ferreira,et al.  Molecular modeling and structure-activity relationships for a series of benzimidazole derivatives as cruzain inhibitors. , 2017, Future medicinal chemistry.

[34]  A. Galetin,et al.  Contribution of intestinal cytochrome p450-mediated metabolism to drug-drug inhibition and induction interactions. , 2010, Drug metabolism and pharmacokinetics.

[35]  V. Berdini,et al.  Crystal structure of Schistosoma purine nucleoside phosphorylase complexed with a novel monocyclic inhibitor. , 2009, Acta tropica.

[36]  Leonardo L. G. Ferreira,et al.  Advances and Progress in Chagas Disease Drug Discovery. , 2016, Current topics in medicinal chemistry.

[37]  D C Swinney,et al.  Phenotypic vs. Target‐Based Drug Discovery for First‐in‐Class Medicines , 2013, Clinical pharmacology and therapeutics.

[38]  Richard Svensson,et al.  Introduction to in vitro estimation of metabolic stability and drug interactions of new chemical entities in drug discovery and development. , 2006, Pharmacological reports : PR.

[39]  Adriano D Andricopulo,et al.  Pharmacokinetic properties and in silico ADME modeling in drug discovery. , 2013, Medicinal chemistry (Shariqah (United Arab Emirates)).

[40]  A. Kamal,et al.  Podophyllotoxin derivatives: a patent review (2012 – 2014) , 2015, Expert opinion on therapeutic patents.

[41]  Alessandro Pedretti,et al.  Reactions and enzymes in the metabolism of drugs and other xenobiotics. , 2012, Drug discovery today.

[42]  G. Loake,et al.  Paclitaxel: biosynthesis, production and future prospects. , 2014, New biotechnology.

[43]  John P. Overington,et al.  The genome of the blood fluke Schistosoma mansoni , 2009, Nature.

[44]  Yousef Ahmed Fouad,et al.  Revisiting the hallmarks of cancer. , 2017, American journal of cancer research.

[45]  Adriano D Andricopulo,et al.  Consensus hologram QSAR modeling for the prediction of human intestinal absorption. , 2012, Bioorganic & medicinal chemistry letters.

[46]  David T Stanton,et al.  QSAR and QSPR model interpretation using partial least squares (PLS) analysis. , 2012, Current computer-aided drug design.

[47]  J. McKerrow,et al.  A Cysteine Protease Inhibitor Cures Chagas' Disease in an Immunodeficient-Mouse Model of Infection , 2007, Antimicrobial Agents and Chemotherapy.

[48]  Glaucius Oliva,et al.  Quantitative structure-activity relationships for a series of inhibitors of cruzain from Trypanosoma cruzi: molecular modeling, CoMFA and CoMSIA studies. , 2009, Journal of molecular graphics & modelling.

[49]  R. Juliano Pharmaceutical innovation and public policy: The case for a new strategy for drug discovery and development , 2013 .

[50]  Robert A. Copeland,et al.  Enzymes: A Practical Introduction to Structure, Mechanism, and Data Analysis , 1996 .

[51]  David J Newman,et al.  Natural products as sources of new drugs over the 30 years from 1981 to 2010. , 2012, Journal of natural products.

[52]  Nobhojit Roy,et al.  The Global Burden of Cancer 2013. , 2015, JAMA oncology.

[53]  Dieter Lang,et al.  Predicting drug metabolism: experiment and/or computation? , 2015, Nature Reviews Drug Discovery.

[54]  You-sheng Liang,et al.  Susceptibility or resistance of praziquantel in human schistosomiasis: a review , 2012, Parasitology Research.

[55]  J. McKerrow,et al.  The Trypanosoma cruzi Protease Cruzain Mediates Immune Evasion , 2011, PLoS pathogens.

[56]  K. Graef,et al.  Fostering innovative product development for neglected tropical diseases through partnerships. , 2016, Pharmaceutical patent analyst.

[57]  C. Wiesmann,et al.  The discovery of first-in-class drugs: origins and evolution , 2014, Nature Reviews Drug Discovery.

[58]  Leonardo G Ferreira,et al.  Discovery of Novel Antischistosomal Agents by Molecular Modeling Approaches. , 2016, Trends in parasitology.

[59]  Tim W. Overton,et al.  Recombinant protein production in bacterial hosts. , 2014, Drug discovery today.