| Autor: |
Charbe NB; Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics (Lake Nona), University of Florida, Orlando, FL 32827, USA., Zacconi FC; Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile.; Institute for Biological and Medical Engineering, Schools of Engineering, Medicine and Biological Sciences, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile., Kowthavarapu VK; Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics (Lake Nona), University of Florida, Orlando, FL 32827, USA., Gupta C; Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics (Lake Nona), University of Florida, Orlando, FL 32827, USA., Palakurthi SS; Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA., Satheeshkumar R; Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA., Lokwani DK; Department of Pharmaceutical Chemistry, Rajarshi Shahu College of Pharmacy, Buldana 443001, India., Tambuwala MM; Lincoln Medical School, University of Lincoln, Brayford Pool Campus, Lincoln LN6 7TS, UK., Palakurthi S; Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA. |
| Abstrakt: |
The primary cause of atherosclerotic cardiovascular disease (ASCVD) is elevated levels of low-density lipoprotein cholesterol (LDL-C). Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in this process by binding to the LDL receptor (LDL-R) domain, leading to reduced influx of LDL-C and decreased LDL-R cell surface presentation on hepatocytes, resulting higher circulating levels of LDL-C. As a consequence, PCSK9 has been identified as a crucial target for drug development against dyslipidemia and hypercholesterolemia, aiming to lower plasma LDL-C levels. This research endeavors to identify promising inhibitory candidates that target the allosteric site of PCSK9 through an in silico approach. To start with, the FDA-approved Drug Library from Selleckchem was selected and virtually screened by docking studies using Glide extra-precision (XP) docking mode and Smina software (Version 1.1.2). Subsequently, rescoring of 100 drug compounds showing good average docking scores were performed using Gnina software (Version 1.0) to generate CNN Score and CNN binding affinity. Among the drug compounds, amikacin, bestatin, and natamycin were found to exhibit higher docking scores and CNN affinities against the PCSK9 enzyme. Molecular dynamics simulations further confirmed that these drug molecules established the stable protein-ligand complexes when compared to the apo structure of PCSK9 and the complex with the co-crystallized ligand structure. Moreover, the MM-GBSA calculations revealed binding free energy values ranging from -84.22 to -76.39 kcal/mol, which were found comparable to those obtained for the co-crystallized ligand structure. In conclusion, these identified drug molecules have the potential to serve as inhibitors PCSK9 enzyme and these finding could pave the way for the development of new PCSK9 inhibitory drugs in future in vitro research. |
