Computer-Aided Drug Design (CADD) to De-Orphanize Marine Molecules: Finding Potential Therapeutic Agents for Neurodegenerative and Cardiovascular Diseases.

Laura Llorach-Pares,Conxita Avila,Alfons Nonell-Canals,Melchor Sanchez-Martinez

doi:10.3390/md20010053

Laura Llorach-Pares, Conxita Avila + Show 2 more

Open Access

https://doi.org/10.3390/md20010053

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Abstract

Computer-aided drug design (CADD) techniques allow the identification of compounds capable of modulating protein functions in pathogenesis-related pathways, which is a promising line on drug discovery. Marine natural products (MNPs) are considered a rich source of bioactive compounds, as the oceans are home to much of the planet’s biodiversity. Biodiversity is directly related to chemodiversity, which can inspire new drug discoveries. Therefore, natural products (NPs) in general, and MNPs in particular, have been used for decades as a source of inspiration for the design of new drugs. However, NPs present both opportunities and challenges. These difficulties can be technical, such as the need to dive or trawl to collect the organisms possessing the compounds, or biological, due to their particular marine habitats and the fact that they can be uncultivable in the laboratory. For all these difficulties, the contributions of CADD can play a very relevant role in simplifying their study, since, for example, no biological sample is needed to carry out an in-silico analysis. Therefore, the amount of natural product that needs to be used in the entire preclinical and clinical study is significantly reduced. Here, we exemplify how this combination between CADD and MNPs can help unlock their therapeutic potential. In this study, using a set of marine invertebrate molecules, we elucidate their possible molecular targets and associated therapeutic potential, establishing a pipeline that can be replicated in future studies.

Highlights

In the context of drug discovery, the progression from basic research to market through the various pre-clinical and clinical phases takes tens of years and costs billions of dollars [1]
Based on the idea of that marine molecules are a rich source of potential drugs [17,18,21,28] and on the fact of Computer-aided drug design (CADD) techniques have been used to successfully de-orphanize natural products (NPs) [29,30,31,32,33,34], the aim of the present study is (1) to disentangle the possible therapeutic potential of a set of marine molecules, as well as (2) to devise a plausible computational workflow for future studies
Our results indicate that all the marine molecules analyzed here appear to have a certain toxic propensity, albeit low in most cases

Summary

Introduction

In the context of drug discovery, the progression from basic research to market through the various pre-clinical and clinical phases takes tens of years and costs billions of dollars [1]. This constitutes a huge problem for the development of new treatments, becoming a social problem because of its potential influence on reducing the high number of unmet medical needs. (CADD) techniques, used at different stages of the drug discovery process (Figure 1), helps to mitigate this overall cost [2]. They are mostly used in the pre-clinical phase, there is increasing potential for their use in clinical phases [6].

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