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, 36 (16), 4303-4319

Unravelling Novel Congeners From Acetyllysine Mimicking Ligand Targeting a Lysine Acetyltransferase PCAF Bromodomain

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Unravelling Novel Congeners From Acetyllysine Mimicking Ligand Targeting a Lysine Acetyltransferase PCAF Bromodomain

Venkatesan Suryanarayanan et al. J Biomol Struct Dyn.

Abstract

p300/CBP Associated Factor (PCAF) bromodomain (BRD), a lysine acetyltransferases, has emerged as a promising drug target as its dysfunction is linked to onset and progression of several diseases like cancer, diabetes, AIDS, etc. In this study, a three featured E-Pharmacophore (ARR) was generated based on acetyllysine mimicking inhibitor of PCAF BRD which is available as co-crystal structure (PDB ID: 5FDZ). It was used for filtering small molecule databases followed by molecular docking and consequently validated using enrichment calculation. The resulted hits were found to be congeners which show the predictive power of E-Pharmacophore hypothesis. Further, Induced Fit Docking method, Binding energy calculation, ADME prediction, Single Point Energy calculation and Molecular Dynamics simulation were performed to find better hits against PCAF BRD. Based on the results, it was concluded that Asn803, Tyr809 and Tyr802 along with a water molecule (HOH1001) plays crucial role in binding with inhibitor. It is also proposed that four hits from Life Chemicals database namely, F2276-0099, F2276-0008, F2276-0104 and F2276-0106 could act as potent drug molecules for PCAF BRD. Thus, the present study is strongly believed to have bright impact on rational drug design of potent and novel congeners of PCAF BRD inhibitors.

Keywords: ADME; Adsorption distribution metabolism and excretion; AIDS; Acquired immune deficiency syndrome; BEDROC; Boltzmann-enhanced discrimination of receiver operating characteristic; BET; Bromo- and extra-terminal domain; BRD; Bromodomain; DFT; Density functional theory; E-pharmacophore; EF; Enrichment factor; FPF; False positive fractions; GB/SA; Generalized-born/surface area; HAT; Histone acetyltransferase; HIV; Human immunodeficiency virus; HOMO; Highest occupied molecular orbital; HTVS; High throughput virtual screening; IFD; Induced fit docking; LUMO; Lowest unoccupied molecular orbital; Lysine acetyltransferase; MESP; Molecular electrostatic potential; NUT; Nuclear protein in testis; OPLS; Optimized potentials for liquid simulations; PBC; Periodic boundary condition; PCAF bromodomain; PCAF; p300/CBP associated factor; PME; Particle mesh Ewald; RESPA; Reference system propagator algorithm; ROC; Receiver operating characteristic; SBVS; Structure-based virtual screening; SGB; Surface generalized born; SP; Standard precision; SPE; Single-point energy calculation; TPF; True positive fractions; XP; Extra precision; density functional theory; molecular dynamics simulation; vdW; van der Waals.

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