Exploring Ruthenium-based organometallic inhibitors against Plasmodium Calcium Dependent Kinase 2 (PfCDPK2): a combined ensemble docking, QM paramterization and molecular dynamics study

Abstract

Recent advances in the metal-organic framework (MOF) have accelerated the discovery of novel metal-based anticancer, antibacterial and antimalarial compounds. This is substantiated by many serendipitously discovered metals (Ru, Rh, and Ir) based inhibitors that established the importance of metal inserted into the known organic scaffold. Conversely, it is possible to design novel bioactive compounds by mimicking hypervalent carbon atoms by transition metals. This process can be facilitated by computational drug discovery by treating metal center using optimized parameters that can be used for molecular docking and molecular dynamics simulations. Further, the method can be plugged with high computational power and refined algorithms to interpret chemical phenomena with atomic-level insights. In the present work, we have demonstrated an approach for parameterizing three organometallic ligands (FLL, E52, and staurosporine) using MCPB.py. In particular, we report that E52 and FLL have a better shape complimentary and affinity compared to staurosporine identified inhibitor (staurosporine) against Calcium-dependent protein kinases 2 (CDPK2). This study also revealed that a flexible approach (ensemble) outperforms for the given target with dynamic movements. The calculated MMPBSA energies for staurosporine, FLL and E52 were −66.461 ± 2.192, −67.182 ± 1.971 and −91.339 ± 2.745 kcal/mol respectively.

Computational investigation of binding of chloroquinone and hydroxychloroquinone against PLPro of SARS-CoV-2

“…The GROMOS algorithm (Daura et al., 1999 ) was used to determine the dominant conformation with Cα RMSD cut-off value 0.15 nm. Further, Principal Component Analysis (PCA) or Essential Dynamics (ED) analysis was carried out to understand the collective and overall motion, as reported in our previous study using ‘gmx covar’ and ‘gmx anaeig’ tools (Patel et al., 2020 ). PCA reduces the complexity of the data and results in the concerted motion indicating important structural changes.…”

Identification of natural inhibitors against prime targets of SARS-CoV-2 using molecular docking, molecular dynamics simulation and MM-PBSA approaches

“…The GROMOS algorithm (Daura et al, 1999) was used to determine the dominant conformation with Ca RMSD cut-off value 0.15 nm. To understand the collective and overall motion for all the MDS systems, Principal Component Analysis (PCA) or Essential Dynamics (ED) analysis was carried out as reported in our previous study using 'gmxcovar' and 'gmxanaeig' tools (Manhas et al, 2019;Patel et al, 2020). PCA reduces the complexity of the data and results in the concerted motion in the MDS which are correlated and significant for biological functions.…”

Plant‐Based Natural Bioactive Compounds 2,4‐Ditert‐Butylphenolas: A Potential Candidates Against SARS‐Cov‐2019

“… [37] . Hydrogen bond is considered as a crucial type of interaction in drug discovery and development process, as of their strong influence on drug likeliness properties [38] , [39] . So finally our results work aims to demonstrate in identifying novel structures which are having similar structural feature with similar activity with respect to the compounds 2,4-Ditert-butylphenol that are shown best binding energy with the receptors spike protein respectively.…”