In-Silico Approaches for the Screening and Discovery of Broad-Spectrum Marine Natural Product Antiviral Agents Against Coronaviruses

Abstract

The urgent need for SARS-CoV-2 controls has led to a reassessment of approaches to identify and develop natural product inhibitors of zoonotic, highly virulent, and rapidly emerging viruses. There are yet no clinically approved broad-spectrum antivirals available for beta-coronaviruses. Discovery pipelines for pan-virus medications against a broad range of betacoronaviruses are therefore a priority. A variety of marine natural product (MNP) small molecules have shown inhibitory activity against viral species. Access to large data caches of small molecule structural information is vital to finding new pharmaceuticals. Increasingly, molecular docking simulations are being used to narrow the space of possibilities and generate drug leads. Combining in-silico methods, augmented by metaheuristic optimization and machine learning (ML) allows the generation of hits from within a virtual MNP library to narrow screens for novel targets against coronaviruses. In this review article, we explore current insights and techniques that can be leveraged to generate broad-spectrum antivirals against betacoronaviruses using in-silico optimization and ML. ML approaches are capable of simultaneously evaluating different features for predicting inhibitory activity. Many also provide a semi-quantitative measure of feature relevance and can guide in selecting a subset of features relevant for inhibition of SARS-CoV-2.

Manzamine-A Alters In Vitro Calvarial Osteoclast Function

“…Manzamine-A was produced following previously published protocols. ,, Purified manzamine was then transformed into its hydrochloride salt and recrystallized to reach high purity (>99%) and optimized aqueous solubility for use in planned experimentation as described previously. ,, …”

“…In contrast, the differentiated osteoclast is nonmitotic and the cell performs its function of degrading mineralized matrix, after which it detaches from the bone surface and migrates to another bone area of resorption or undergoes programmed cell death. 70 Given our previous data, 59,71,72 we now extend our characterization of cell-specific effects of MA on the osteoclast lineage using in vitro concentration exposures and functional assays. Using the preosteoclast and osteoclast, we hypothesized that MA would alter cell viability and function of preosteoclasts but would have less robust effects on the differentiated osteoclast cultures.…”

“…Given our previous data, ,, we now extend our characterization of cell-specific effects of MA on the osteoclast lineage using in vitro concentration exposures and functional assays. Using the preosteoclast and osteoclast, we hypothesized that MA would alter cell viability and function of preosteoclasts but would have less robust effects on the differentiated osteoclast cultures.…”

Antiherpetic Activity of a Root Exudate from Solanum lycopersicum

“…Within this framework, herbal medicines and purified natural products derived from plants, marine organisms, and other natural sources have garnered considerable attention as a rich resource for the development of innovative antiviral drugs. This includes a diverse array of substances, including essential oils, plant extracts, small peptides from animal sources, bacteriocins, and several categories of plant compounds (such as alkaloids, triterpenoids, flavonoids, and phenols) renowned for their antimicrobial and antiviral properties [ 8 , 9 , 10 ]. The use of natural compounds as antivirals presents several advantages over synthetic drugs.…”

Informatics and Computational Approaches for the Discovery and Optimization of Natural Product-Inspired Inhibitors of the SARS-CoV-2 2′-O-Methyltransferase

“…Presented here is a continuation of previous work described in the viewpoint “Contemporary Approaches to the Discovery and Development of Broad-Spectrum Natural Product Prototypes for the Control of Coronaviruses” . The intent of that earlier work was to describe strategies for efficiently identifying natural products using in silico molecular modeling techniques typically used in rational drug design with synthetic molecule libraries . This effort was also intended to address production limitations commonly encountered in natural product screening where access to source material and the labor of isolating large sets of compounds can quickly outstrip an academic laboratory’s research capacity. − By using a computational approach, efforts were focused on a refined number of compounds that were ultimately selected for in vitro evaluation and later target identification.…”