Structure-based virtual screening against multiple Plasmodium falciparum kinases reveals antimalarial compounds.

The continuous emergence of resistance against most frontline antimalarial drugs has led to countless deaths in malaria-endemic countries, counting 619,000 deaths in 2021, with mutation in drug targets being the sole cause. As mutation is correlated frequently with fitness cost, the likelihood of mutation emergence in multiple targets at a time is extremely low. Hence, multitargeting compounds may seem promising to address drug resistance issues with additional benefits like increased efficacy, improved safety profile, and the requirement of fewer pills compared to traditional single and combinational drugs. In this study, we attempted to use the High Throughput Virtual Screening approach to predict multitarget inhibitors against six chemically validated Plasmodium falciparum (Pf) kinases (PfPKG, PfMAP2, PfCDPK4, PfTMK, PfPK5, PfPI4K), resulting in 21 multitargeting hits. The molecular dynamic simulation of the top six complexes (Myricetin-MAP2, Quercetin-CDPK4, Myricetin-TMK, Quercetin-PKG, Salidroside-PK5, and Salidroside-PI4K) showed stable interactions. Moreover, hierarchical clustering reveals the structural divergence of the compounds from the existing antimalarials, indicating less chance of cross-resistance. Additionally, the top three hits were validated through parasite growth inhibition assays, with quercetin and myricetin exhibiting an IC50 value of 1.84 and 3.93 µM, respectively.

The Custom R Group Enumeration with Various R Group Libraries at Designated Sites on Amphotericin B.

BACKGROUND: Amphotericin B is a gold-standard drug, particularly for the treatment of systemic fungal infections. However, its low solubility and permeability limit its application. To improve its bioavailability, AmB may be conjugated with various water-soluble auxiliary groups. METHODS: Custom R group Enumeration was used at the designated sites of Amphotericin B. The designated sites taken into consideration are the carboxyl moiety of the aglycone part and the amine moiety of the glycone part of Amphotericin B for Enumeration purposes. The enumerated molecules were subjected to QikProp properties. RESULTS: We identified fourteen hits with improved predicted aqueous solubility and cell permeability. CONCLUSION: Enumeration might be applicable in improving bioavailability, which could lead to the oral formulation of the Amphotericin B drug.

Chemical and Physical Approaches for Improved Biopharmaceutical Activity of Amphotericin B: Current and Future Prospective.

Over the last 50 years, the number of patients with mycotic infections has gradually increased. Amphotericin-B is a gold-standard drug used in serious systemic fungal infections. However, limited solubility and permeability are challenging issues associated with Amphotericin-B. Chemical modification is one of the ways to get its broader applicability and improved physicochemical properties. The review article provides a comprehensive overview of the chemical modification approach for investigating the mechanism of action, biological activity, bioavailability, and toxicity of Amphotericin B. Further, several drug delivery approaches have also been utilized to provide better therapeutic outcomes. This gives an overview of chemical approaches for exploring various factors associated with Amphotericin B and information on its drug delivery approaches for improved biopharmaceutical outcomes.