10.6084/m9.figshare.5640178.v2
Saleem Iqbal
Saleem
Iqbal
Dhanabalan Anantha Krishnan
Dhanabalan Anantha
Krishnan
Krishnasamy Gunasekaran
Krishnasamy
Gunasekaran
Identification of potential PKC inhibitors through pharmacophore designing, 3D-QSAR and molecular dynamics simulations targeting Alzheimer’s disease
Taylor & Francis Group
2017
Alzheimer’s disease
PKCθ
staurosporine
pyrrole
PBVS
MM-GBSA
molecular dynamics simulation
AD, Alzheimer’s disease
PKC, protein kinase C
CPH, common pharmacophore hypothesis
HBD, hydrogen bond donor
SD, standard deviation
RMSD, root-mean-square deviation
ROC, receiver operating characteristic
PBVS, pharmacophore-based virtual screening
XP, extra precision
IFD, induced fit docking
MM-GBSA, molecular mechanics generalized born surface area
MD, molecular dynamics simulation
RMSF, root-mean-square fluctuation
PSA, polar surface area
2017-12-13 11:40:45
Journal contribution
https://tandf.figshare.com/articles/journal_contribution/Identification_of_potential_PKC_inhibitors_through_Pharmacophore_designing_3D-QSAR_and_Molecular_Dynamics_simulations_targeting_Alzheimer_s_disease/5640178
<p>Protein kinases are ubiquitously expressed as Serine/Threonine kinases, and play a crucial role in cellular activities. Protein kinases have evolved through stringent regulation mechanisms. Protein kinases are also involved in tauopathy, thus are important targets for developing Anti-Alzheimer’s disease compounds. Structures with an indole scaffold turned out to be potent new leads. With the aim of developing new inhibitors for human protein kinase C, here we report the generation of four point 3D geometric featured pharmacophore model. In order to identify novel and potent PKCθ inhibitors, the pharmacophore model was screened against 80,000,00 compounds from various chemical databases such as., ZINC, SPEC, ASINEX, which resulted in 127 compound hits, and were taken for molecular docking filters (HTVS, XP docking). After in-depth analysis of binding patterns, induced fit docking (flexible) was employed for six compounds along with the cocrystallized inhibitor. Molecular docking study reveals that compound 6F found to be tight binder at the active site of PKCθ as compared to the cocrystal and has occupancy of 90 percentile. MM-GBSA also confirmed the potency of the compound 6F as better than cocrystal. Molecular dynamics results suggest that compound 6F showed good binding stability of active sites residues similar to cocrystal 7G compound. Present study corroborates the pharmacophore-based virtual screening, and finds the compound 6F as a potent Inhibitor of PKC, having therapeutic potential for Alzheimer’s disease. Worldwide, 46.8 million people are believed to be living with Alzheimer’s disease. When elderly population increases rapidly and neurodegenerative burden also increases in parallel, we project the findings from this study will be useful for drug developing efforts targeting Alzheimer’s disease.</p>