Drug Design for Neuropathic Pain Regulation from Traditional Chinese Medicine

Abstract

FAAH-like anandamide transporter (FLAT) regulates anandamide transport for hydrolysis and may be an attractive drug target for pain regulation. We aimed to discover potential FLAT antagonists from traditional Chinese medicine (TCM) using virtual screening, ligand-based drug design and molecular dynamics simulation (MD). Guineensine and Retrofractamide A exhibited high Dock Scores in FLAT. Consensus from multiple linear regression (MLR; R2 = 08973) and support vector machine (SVM; R2 = 0.7988) showed similar bioactivities for Guineensine and the FAAH-1 inhibitor (9Z)-1-(5-pyridin-2-yl-1,3,4-oxadiazol-2-yl)octadec-9-en-1-one. Contour of Guineensine to CoMFA and CoMSIA features also imply bioactivity. MD revealed shake or vibration in the secondary structure of FLAT complexed with Guineensine and (9Z)-1-(5-pyridin-2-yl-1,3,4-oxadiazol-2-yl)octadec-9-en-1-one. Ligand movement might contribute to protein changes leading to vibration patterns. Violent vibrations leading to an overall decrease in FLAT function could be the underlying mechanism for Guineensine. Here we suggest Guineensine as a drug-like compound with potential application in relieving neuropathic pain by inhibiting FLAT.

RETRACTED: Gentamicin B1 is a minor gentamicin component with major nonsense mutation suppression activity

“…Molecular Dynamics Simulations. Molecular dynamics simulations were performed using GROMACS (20, 21) as described previously (22,23) ) mice (22-30 g) were inoculated s.c. in the lower back with 2 million NCI-H1299 cells stably expressing TP53 R213X in a volume of 50 μL. The site of tumor cell inoculation was monitored daily.…”

Beware of docking!

“…In our experience, translating drug discovery from CADD to clinical trials is difficult. For example, some top potent hits screened by docking from the TCM database failed in the final bioactivity test [20,[22][23][24][25][26][27]. However, if a hit comes first from a bioassay -for example, if it was screened from high-throughput screening (HTS) by 'automation-friendly' robotics, data processing, and control software in vitro -then it is easier to move to in vivo.…”

“…From Figure 4, it seems that only the induced-fit mode will change the shape of the binding pocket. However, the entry into the binding pocket will sometimes change the shape of the binding site, according to simulation from MD experiments [16,19,20,23,31]. When type of shift occurs with ligand binding, rigid docking programs will not provide useful answers.…”

“…However, if a hit comes first from a bioassay -for example, if it was screened from high-throughput screening (HTS) by 'automation-friendly' robotics, data processing, and control software in vitro -then it is easier to move to in vivo. Explaining the underlying biological mechanism is easier and more reasonable [23]. However, given the rise of docking studies, it is important to conduct them with care.…”

First-principles studies of multiferroic and magnetoelectric materials

“…As is well known, classical molecular dynamics simulations describe the process of resolving Newton's equations of motion for many-body systems over a period of time. As one of the most powerful modern computational methods, classical molecular dynamics study has been applied into ultra-precision manufacturing [125], (soft) condensed matter physics [126][127][128], genetic engineering [129], medicine [130], etc. However, its intrinsic dependence of predefined potentials and force fields established by empirical physical data or independent electronic structure calculations not only bring suitable approximation for atomic interactions, but also is a conspicuous shortage owing to the terrible portability of potentials.…”