Development of Monoamine Oxidase B Inhibitors with Antiparkinson Activity

The knowledge of the bioactive conformation for an active hit is relevant because of the easier interpretation and the general quality of the recognition models of protein and ligand. With the aim of investigating potential bioactive conformations without previous structural knowledge of the molecular target, we present herewith a 'protocol' that could be used which includes generation of low-energy conformations, calculations of tridimensional descriptors and investigation of structural similarity via principal component analysis. The protocol was used in the search for potential bioactive conformations. An initial selection of targets was made from a set of protein-ligand complexes with structure deposited in the Protein Data Bank, which was systematically filtered by lead-like rules, resulting in 45 ligands of 8 important therapeutic targets. After extensive optimization of the protocol and parameters of both OMEGA and Pentacle softwares, the best results were obtained for series of compounds such as the beta-trypsin and urokinase inhibitors, which are more structurally related among each other, inside the respective therapeutic class. Future improvements of the protocol, including a suitable choice and combination of robust 3D descriptors, could yield more reliable and less restrictive results, with general and diverse applications in drug design, in particular for improving the 3D-QSAR methodologies as well as virtual screening experiments for a more reliable selection of new lead compounds for different molecular targets.

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Pharmacophore and structure-based drug design, molecular dynamics and admet/tox studies to design novel potential pad4 inhibitors

Barcellos

Santos

Federico

et al. 2018

Journal of Biomolecular Structure and Dynamics

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We have used docking (GLIDE), pharmacophore modeling (Discovery Studio), long trajectory molecular dynamics (Discovery Studio) and ADMET/Tox (QikProp and DEREK) to investigate PAD4 in order to determine potential novel inhibitors and hits. We have carried out virtual screening in the ZINC natural compounds database. Pharmacokinetics and Toxicity of the best hits were assessed using databases implemented in softwares that create models based on chemical structures taking into account consideration about the toxicophoric groups. A wide variety of pharmaceutical relevant properties are determined in order to make decisions about molecular suitability. After screening and analysis, the 6 most promising PAD4 inhibitors are suggested, with strong interactions (pi-stacking, hydrogen bonds, hydrophobic contacts) and suitable pharmacotherapeutic profile as well.

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Development of Monoamine Oxidase B Inhibitors with Antiparkinson Activity

Cited by 5 publications

References 8 publications

Review on Simulation Models for Materials and Biomolecular Study and Design

Review on Simulation Models for Materials and Biomolecular Study and Design

3D descriptors calculation and conformational search to investigate potential bioactive conformations, with application in 3D-QSAR and virtual screening in drug design

Pharmacophore and structure-based drug design, molecular dynamics and admet/tox studies to design novel potential pad4 inhibitors

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