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

Abstract

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.

In silico approaches to develop herbal acaricides against R. (Boophilus) Microplus and In vitro Anti-Tick activities of selected medicinal plants

“…Tick survival is dependent on RmAChE1 as shown by its high affinity for target (acetylcholine; ACh) and higher conversion rates than Rhipicephalus microplus acetylcholinesterase 2 and Rhipicephalus microplus acetylcholinesterase 3 ( Temeyer et al, 2010 ). The development of new acaricides and our understanding of their mechanisms of action are hampered by lack of understanding of RmAChE's crystalline structure ( Ferreira et al, 2018 ). Comparative modelling allows docking technique to be used to analyze antiACh medication molecular interactions at the atomic level, it is critical in overcoming these restrictions ( Schmidt et al, 2014 ).…”

Anti-tick effect and cholinesterase inhibition caused by Prosopis juliflora alkaloids: in vitro and in silico studies

“…The higher affinity with the substrate (acetylcholine; ACh) and higher conversion rates of RmAChE2 and RmAChE3 that were previously observed (Temeyer et al, 2010) suggest that RmAChE1 is very important for tick survival. However, the lack of data on the crystallographic structure of RmAChE limits both the designing of new acaricidal compounds and knowledge of the mechanism of action of these molecules (Williams et al, 2005;Lionta et al, 2014;Ferreira et al, 2018). Thus, comparative modeling (homology modeling) plays a significant role in reducing these limitations because it enables investigation, at the atomic level, of the molecular interactions of anticholinesterase compounds through molecular docking (Schmidt et al, 2014).…”

The Potential of Biologically Active Brazilian Plant Species as a Strategy to Search for Molecular Models for Mosquito Control

“…The design of active compounds is mainly based on the knowledge of the mechanisms by which bioactive molecules interact with their molecular targets [101]. Structure-based drug design by means of molecular modeling is one of the most efficient strategies used to evaluate the interaction of active compounds and its biological target, and improve pharmacodynamics [102]. This is a useful method to identify crucial intermolecular interactions in the process of molecular recognition and for the selection of hits that bind or fit to the target protein binding cavity.…”