In silico identification of phytochemical inhibitors for multidrug-resistant tuberculosis based on novel pharmacophore generation and molecular dynamics simulation studies.

BACKGROUND: Multidrug-resistant tuberculosis (particularly resistant to pyrazinoic acid) is a life-threatening chronic pulmonary disease. Running a marketed regime specifically targets the ribosomal protein subunit-1 (RpsA) and stops trans-translation in the non-mutant bacterium, responsible for the lysis of bacterial cells. However, in the strains of mutant bacteria, this regime has failed in curing TB and killing pathogens, which may only because of the ala438 deletion, which inhibit the binding of pyrazinoic acid to the RpsA active site. Therefore, such cases of tuberculosis need an immediate and effective regime. OBJECTIVE: This study has tried to determine and design such chemotypes that are able to bind to the mutant RpsA protein. METHODS: For these purposes, two phytochemical databases, i.e., NPASS and SANCDB, were virtually screened by a pharmacophore model using an online virtual screening server Pharmit. RESULTS: The model of pharmacophore was developed using the potential inhibitor (zr115) for the mutant of RpsA. Pharmacophore-based virtual screening results into 154 hits from the NPASS database, and 22 hits from the SANCDB database. All the predicted hits were docked in the binding pocket of the mutant RpsA protein. Top-ranked five and two compounds were selected from the NPASS and SANCDB databases respectively. On the basis of binding energies and binding affinities of the compounds, three compounds were selected from the NPASS database and one from the SANCDB database. All compounds were found to be non-toxic and highly active against the mutant pathogen. To further validate the docking results and check the stability of hits, molecular dynamic simulation of three compounds were performed. The MD simulation results showed that all these finally selected compounds have stronger binding interactions, lesser deviation or fluctuations, with greater compactness compared to the reference compound. CONCLUSION: These findings indicate that these compounds could be effective inhibitors for mutant RpsA.

In silico screening of SARS-CoV2 helicase using African natural products: Docking and molecular dynamics approaches.

In the current medical era, there is an urgent necessity to identify new effective drugs to enrich the COVID-19's therapeutic arsenal. The SARS-COV-2 NSP13/helicase enzyme has been identified as a potential target for developing novel COVID-19 inhibitors. In this work, we aimed at endorsing effective natural products with potential inhibitory action towards the NSP13 through the virtual screening of 1012 natural products of botanical and marine origin from the South African Natural Compounds Database (SANCDB). The molecules were docked into the NTPase active site, and the best twelve compounds were chosen for further analysis. Thereafter, a combination of molecular dynamics simulations and MM-GBSA free energy calculations were carried out for a subset of best hits complexed with NSP13 helicase. We believe that the findings of this work will pave the way for additional research and experimental validation of some natural products as viable NSP13 helicase inhibitors.

SANCDB: an update on South African natural compounds and their readily available analogs.

BACKGROUND: South African Natural Compounds Database (SANCDB; https://sancdb.rubi.ru.ac.za/ ) is the sole and a fully referenced database of natural chemical compounds of South African biodiversity. It is freely available, and since its inception in 2015, the database has become an important resource to several studies. Its content has been: used as training data for machine learning models; incorporated to larger databases; and utilized in drug discovery studies for hit identifications. DESCRIPTION: Here, we report the updated version of SANCDB. The new version includes 412 additional compounds that have been reported since 2015, giving a total of 1012 compounds in the database. Further, although natural products (NPs) are an important source of unique scaffolds, they have a major drawback due to their complex structure resulting in low synthetic feasibility in the laboratory. With this in mind, SANCDB is, now, updated to provide direct links to commercially available analogs from two major chemical databases namely Mcule and MolPort. To our knowledge, this feature is not available in other NP databases. Additionally, for easier access to information by users, the database and website interface were updated. The compounds are now downloadable in many different chemical formats. CONCLUSIONS: The drug discovery process relies heavily on NPs due to their unique chemical organization. This has inspired the establishment of numerous NP chemical databases. With the emergence of newer chemoinformatic technologies, existing chemical databases require constant updates to facilitate information accessibility and integration by users. Besides increasing the NPs compound content, the updated SANCDB allows users to access the individual compounds (if available) or their analogs from commercial databases seamlessly.