PCSK9 inhibitors as safer therapeutics for atherosclerotic cardiovascular disease (ASCVD): Pharmacophore design and molecular dynamics analysis.

Cardiovascular disorders are still challenging and are among the deadly diseases. As a major risk factor for atherosclerotic cardiovascular disease, dyslipidemia, and high low-density lipoprotein cholesterol in particular, can be prevented primary and secondary by lipid-lowering medications. Therefore, insights are still needed into designing new drugs with minimal side effects. Proprotein convertase subtilisin/kexin 9 (PCSK9) enzyme catalyses protein-protein interactions with low-density lipoprotein, making it a critical target for designing promising inhibitors compared to statins. Therefore, we screened for potential compounds using a redesigned PCSK9 conformational behaviour to search for a significantly extensive chemical library and investigated the inhibitory mechanisms of the final compounds using integrated computational methods, from ligand essential functional group screening to all-atoms MD simulations and MMGBSA-based binding free energy. The inhibitory mechanisms of the screened compounds compared with the standard inhibitor. K31 and K34 molecules showed stronger interactions for PCSK9, having binding energy (kcal/mol) of -33.39 and -63.51, respectively, against -27.97 of control. The final molecules showed suitable drug-likeness, non-mutagenesis, permeability, and high solubility values. The C-α atoms root mean square deviation and root mean square fluctuation of the bound-PCSK9 complexes showed stable and lower fluctuations compared to apo PCSK9. The findings present a model that unravels the mechanism by which the final molecules proposedly inhibit the PCSK9 function and could further improve the design of novel drugs against cardiovascular diseases.

Microbes, not humans: exploring the molecular basis of Pseudouridimycin selectivity towards bacterial and not human RNA polymerase.

OBJECTIVE: Bacterial RNA polymerase (bRNAP) represent a crucial target for curtailing microbial activity but its structural and sequence similarities with human RNA polymerase II (hRNAPII) makes it difficult to target. Recently, Pseudouridimycin (PUM), a novel nucleoside analogue was reported to selectively inhibit bRNAP and not hRNAP. Till date, underlying mechanisms of PUM selectivity remains unresolved, hence the aim of this study. RESULTS: Using sequence alignment method, we observed that the ß' of bRNAP and the RPB1 subunits of hRNAPII were highly conserved while the ß and RPB2 subunits of both proteins were also characterized by high sequence variations. Furthermore, the impact of these variations on the differential binding of PUM was evaluated using MMPB/SA binding free energy and per-residue decomposition analysis. These revealed that PUM binds better to bRNAP than hRNAP with prominent bRNAP active site residues that contributed the most to PUM binding and stabilization lacking in hRNAPII active site due to positional substitution. Also, the binding of PUM to hRNAP was characterized by the formation of unfavorable interactions. In addition, PUM assumed favorable orientations that possibly enhanced its mobility towards the hydrophobic core region of bRNAP. On the contrary, unfavorable intramolecular interactions characterize PUM orientations at the binding site of hRNAPII, which could restrict its movement due to electrostatic repulsions. CONCLUSION: These findings would enhance the design of potent and selective drugs for broad-spectrum antimicrobial activity.