Pharmacoinformatics based elucidation and designing of potential inhibitors against Plasmodium falciparum to target importin α/ß mediated nuclear importation.

Plasmodium falciparum, the prime causative agent of malaria, is responsible for 4, 05,000 deaths per year and fatality rates are higher among the children aged below 5 years. The emerging distribution of the multi-drug resistant P. falciparum becomes a worldwide concern, so the identification of unique targets and novel inhibitors is a prime need now. In the present study, we have employed pharmacoinformatics approaches to analyze 265 lead-like compounds from PubChem databases for virtual screening. Thereafter, 15 lead-like compounds were docked within the active side pocket of importin alpha. Comparative ligand properties and absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile were also assessed. Finally, a novel inhibitor was designed and assessed computationally for its efficacy. From the comparative analysis we have found that our screened compounds possess better results than the existing lead ivermectin; having the highest binding energy of -15.6 kcal/mol, whereas ivermectin has -12.4 kcal/mol. The novel lead compound possessed more fascinating output without deviating any of the rules of Lipinski. It also possessed higher bioavailability and the drug-likeness score of 0.55 and 0.71, respectively compared to ivermectin. Furthermore, the binding study was confirmed by molecular dynamics simulation over 25 ns by evaluating the stability of the complex. Finally, all the screened compounds and the novel compound showed promising ADMET properties likewise. To end, we hope that our proposed screened compounds, as well as the novel compound, might give some advances to treat malaria efficiently in vitro and in vivo.

Design of novel viral attachment inhibitors of the spike glycoprotein (S) of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) through virtual screening and dynamics.

To date, the global COVID-19 pandemic has been associated with 11.8 million cases and over 545481 deaths. In this study, we have employed virtual screening approaches and selected 415 lead-like compounds from 103 million chemical substances, based on the existing drugs, from PubChem databases as potential candidates for the S protein-mediated viral attachment inhibition. Thereafter, based on drug-likeness and Lipinski's rules, 44 lead-like compounds were docked within the active side pocket of the viral-host attachment site of the S protein. Corresponding ligand properties and absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile were measured. Furthermore, four novel inhibitors were designed and assessed computationally for efficacy. Comparative analysis showed the screened compounds in this study maintain better results than the proposed mother compounds, VE607 and SSAA09E2. The four designed novel lead compounds possessed more fascinating output without deviating from any of Lipinski's rules. They also showed higher bioavailability and the drug-likeness score was 0.56 and 1.81 compared with VE607 and SSAA09E2, respectively. All the screened compounds and novel compounds showed promising ADMET properties. Among them, the compound AMTM-02 was the best candidate, with a docking score of -7.5 kcal/mol. Furthermore, the binding study was verified by molecular dynamics simulation over 100 ns by assessing the stability of the complex. The proposed screened compounds and the novel compounds may give some breakthroughs for the development of a therapeutic drug to treat SARS-CoV-2 proficiently in vitro and in vivo.