Infectious agents such as SARS-CoV, MERS-CoV, and SARS-CoV-2 have emerged in recent years causing epidemics with high mortality rates. The quick development of novel therapeutic compounds is required in the fight against such pathogenic agents. Unfortunately, the traditional drug development methods are time-consuming and expensive. In this study, computational algorithms were utilized for virtual screening of a library of natural compounds in the ZINC database for their affinity towards SARS-CoV-2 M^pro. Compounds such as cinanserin, nelfinavir, baicalin, baicalein, candesartan cilexetil, chloroquine, dipyridamole, and hydroxychloroquine have the ability to prevent SARS-CoV-2 M^pro from facilitating COVID 19 infection; thus, they treat COVID 19. However, these drugs majorly act to reduce the symptoms of the disease. No anti-viral drug against COVID 19 virus infection has been discovered and approved. Therefore, this study sought to explore natural inhibitors of SARS-CoV-2 M^pro to develop a pharmacophore model for virtual screening of natural compounds in the ZINC database as potential candidates for SARS-CoV-2 M^pro inhibitors and as therapeutic molecules against COVID 19. This study undertook in silico methods to identify the best anti-viral candidates targeting SAR-CoV-2 M^pro from natural sources in the ZINC database. Initially, reported anti-SARS-CoV-2 M^pro molecules were integrated into designing a pharmacophore model utilizing PharmaGist. Later, the pharmacophore model was loaded into ZINCPHARMER and screened against the ZINC database to identify new probable drug candidates. The root means square deviation (RMSD) values of the potential drug candidates informed the selection of some of them, which were docked with SARS-CoV-2 M^pro to comprehend their interactions. From the molecular docking results, the top four candidates (ZINC000254823011, ZINC000072307130, ZINC000013627512, and ZINC000009418994) against SARS-CoV-2 M^pro, with binding energies ranging from 8.2kcal/mol to 8.6kcal/mol, were examined for their oral bioavailability and other pharmacokinetic properties. Consequently, ZINC000072307130 emerged as the only orally bioavailable drug candidate with desirable pharmacokinetic properties. This candidate drug was used to perform MD simulations, and the outcomes revealed that ZINC000072307130 formed a stable complex with the viral main protease. Consequently, ZINC000072307130 emerges as a potential anti-SARS-CoV-2 M^pro inhibitor for the production of new COVID 19 drugs.

The coronavirus disease 2019 (COVID-19) is a severe worldwide pandemic. Due to the emergence of various SARS-CoV-2 variants and the presence of only one Food and Drug Administration (FDA) approved anti-COVID-19 drug (remdesivir), the disease remains a mindboggling global public health problem. Developing anti-COVID-19 drug candidates that are effective against SARS-CoV-2 and its various variants is a pressing need that should be satisfied. This systematic review assesses the existing literature that used in silico models during the discovery procedure of anti-COVID-19 drugs. Cochrane Library, Science Direct, Google Scholar, and PubMed were used to conduct a literature search to find the relevant articles utilizing the search terms In silico model, COVID-19, Anti-COVID-19 drug, Drug discovery, Computational drug designing, and Computer-aided drug design. Studies published in English between 2019 and December 2022 were included in the systematic review. From the 1120 articles retrieved from the databases and reference lists, only 33 were included in the review after the removal of duplicates, screening, and eligibility assessment. Most of the articles are studies that use SARS-CoV-2 proteins as drug targets. Both ligand-based and structure-based methods were utilized to obtain lead anti-COVID-19 drug candidates. Sixteen articles also assessed absorption, distribution, metabolism, excretion, toxicity (ADMET), and drug-likeness properties. Confirmation of the inhibitory ability of the candidate leads by in vivo or in vitro assays was reported in only five articles. Virtual screening, molecular docking (MD), and molecular dynamics simulation (MDS) emerged as the most commonly utilized in silico models for anti-COVID-19 drug discovery.

World Health Organization recommend the use of malaria vaccine, Mosquirix, as a malaria prevention strategy. However, Mosquirix has failed to reduce the global burden of malaria because of its inefficacy. The Mosquirix vaccine’s modest effectiveness against malaria, 36% among kids aged 5 to 17 months who need at least four doses, fails to aid malaria eradication. Therefore, highly effective and efficacious malaria vaccines are required. The well-characterized P. falciparum circumsporozoite surface protein can be used to discover adjuvants that can increase the efficacy of Mosquirix. Therefore, the study sought to undertake an in-silico discovery of Plasmodium falciparum circumsporozoite surface protein inhibitors with pharmacological properties on Mosquirix using hierarchical virtual screening and molecular dynamics simulation. Monoclonal antibody L9, an anti-Plasmodium falciparum circumsporozoite surface protein molecule, was used to identify Plasmodium falciparum circumsporozoite surface protein inhibitors with pharmacological properties on Mosquirix during a virtual screening process in ZINCPHARMER that yielded 23 hits. After drug-likeness and absorption, distribution, metabolism, excretion, and toxicity property analysis in the SwissADME web server, only 9 of the 23 hits satisfied the requirements. The 9 compounds were docked with Plasmodium falciparum circumsporozoite surface protein using the PyRx software to understand their interactions. ZINC25374360 (−8.1 kcal/mol), ZINC40144754 (−8.3 kcal/mol), and ZINC71996727 (−8.9 kcal/mol) bound strongly to Plasmodium falciparum circumsporozoite surface protein with binding affinities of less than −8.0 kcal/mol. The stability of these molecularly docked Plasmodium falciparum circumsporozoite surface protein-inhibitor complexes were assessed through molecular dynamics simulation using GROMACS 2022. ZINC25374360 and ZINC71996727 formed stable complexes with Plasmodium falciparum circumsporozoite surface protein. They were subjected to in vitro validation for their inhibitory potential. The IC50 values ranging between 250 and 350 ng/ml suggest inhibition of parasite development. Therefore, the two Plasmodium falciparum circumsporozoite surface protein inhibitors can be used as vaccine adjuvants to increase the efficacy of the existing Mosquirix vaccine. Nevertheless, additional in vivo tests, structural optimization studies, and homogenization analysis are essential to determine the anti-plasmodial action of these adjuvants in humans.

The World Health Organization (WHO) documents malaria as one of the leading causes of high morbidity and mortality worldwide. The disease affects millions and kills thousands of people annually. Efforts to reduce the global burden of malaria have prompted WHO to recommend prevention strategies like using anti-malarial drugs. However, these strategies have been ineffective because of anti-malarial drug resistance. The only efficacious malaria treatment is Artemisinin-based Combination Therapy (ACT). However, the extended ACTs clearance times, linked to the emergence of artemisinin monotherapy resistance recorded most recently in Africa and the Great Mekong region, pose a danger to its efficacy. Therefore, better efficacious malaria drugs are required. Since P. falciparum heat shock protein 90 (PfHsp90) is a well-characterized malaria drugs target, this study uses it to discover more efficacious malaria drugs. An in-silico approach was used to discover PfHsp90 inhibitors with pharmacological properties against Plasmodium malaria using molecular dynamics simulation (MDS) and hierarchical virtual screening. Geldanamycin (GDM), a well-known anti-PfHsp90 compound, was used to identify PfHsp90 inhibitors with pharmacological properties against Plasmodium malaria by screening it against the ZINC database via the ZINCPHARMER web server. This virtual screening process resulted in 17 hits. These ZINCPHARMER hits were subjected to drug-likeness and pharmacokinetics properties analysis in the SwissADME web server, and 9 of them satisfied the requirements. The 9 ZINC compounds were docked with PfHsp90 using the PyRx software to understand their interactions. From the molecular docking results, ZINC09060002 (-8.2 kcal/mol), ZINC72133064 (-7.8 kcal/mol), ZINC72163401 (-7.7 kcal/mol), ZINC72358537 (-8.1 kcal/mol), and ZINC72358557 (-7.6 kcal/mol) had better binding affinities to PfHsp90 than GDM (-7.5 kcal/mol). The stability of these molecularly docked protein-inhibitor complexes was assessed through MDS using GROMACS 2022. ZINC72163401, ZINC72358537, and ZINC72358557 formed stable complexes with PfHsp90. The lead compounds were subjected to in vitro validation for their inhibitory capability. They showed promising inhibition of parasite growth with IC50 values ranging between 200 – 400 ng/ml. In this regard, the three PfHsp90 inhibitors can be used as anti-malarial drugs. However, further structural optimization studies and clinical (in vivo) tests are necessary to ascertain the antimalarial activity of these compounds in humans.