NUCLEAR RECEPTOR SET DOMAIN CONTAINING PROTEIN 2 TRANSITION STATE AND USES THEREOF
Methods and systems for obtaining inhibitors of Nuclear receptor SET Domain containing protein 2 (NSD2) are disclosed where the methods involve designing compounds that resemble the NSD2 transition state.
1 . A system comprising a non-transitory computer-readable medium coupled to one or more data processing apparatus having instructions stored thereon which, when executed by the one or more data processing apparatus, cause the one or more data processing apparatus to perform a method comprising:
(i) obtaining kinetic isotope effects on human Nuclear receptor SET Domain containing protein 2 (NSD2)-catalyzed methylation of histone H3 lysine 36 to obtain the NSD2 transition state structure,
wherein the NSD2 transition state comprises the structure
(ii) obtaining the molecular electrostatic potential at the van der Waals surface computed from the wave function of the NSD2 transition state and the geometric atomic volume of the NSD2 transition state; and
(iiia) identifying from a library of compounds a chemically stable compound that resembles the molecular electrostatic potential at the van der Waals surface computed from the wave function of the NSD2 transition state and the geometric atomic volume of the NSD2 transition state, or
(iiib) designing a chemically stable compound that resembles the molecular electrostatic potential at the van der Waals surface computed from the wave function of the NSD2 transition state and the geometric atomic volume of the NSD2 transition state;
wherein the chemically stable compound that resembles the molecular electrostatic potential at the van der Waals surface computed from the wave function of the NSD2 transition state and the geometric atomic volume of the NSD2 transition state is a putative inhibitor of NSD2.
2 . (canceled)
3 . A computer implemented method performed using a system comprising a non-transitory computer-readable medium coupled to one or more data processing apparatus having instructions stored thereon, the method comprising:
(i) obtaining kinetic isotope effects on human Nuclear receptor SET Domain containing protein 2 (NSD2)-catalyzed methylation of histone H3 lysine 36 to obtain the NSD2 transition state structure,
wherein the NSD2 transition state comprises the structure
(ii) obtaining the molecular electrostatic potential at the van der Waals surface computed from the wave function of the NSD2 transition state and the geometric atomic volume of the NSD2 transition state; and
(iiia) identifying from a library of compounds a chemically stable compound that resembles the molecular electrostatic potential at the van der Waals surface computed from the wave function of the NSD2 transition state and the geometric atomic volume of the NSD2 transition state, or
(iiib) designing a chemically stable compound that resembles the molecular electrostatic potential at the van der Waals surface computed from the wave function of the NSD2 transition state and the geometric atomic volume of the NSD2 transition state;
wherein the chemically stable compound that resembles the molecular electrostatic potential at the van der Waals surface computed from the wave function of the NSD2 transition state and the geometric atomic volume of the NSD2 transition state is a putative inhibitor of NSD2.
4 - 8 . (canceled)
9 . The system of claim 1 , which further comprises synthesizing the compound.
10 . The system of claim 1 , which further comprises testing the compound for inhibitory activity to NSD2.
11 . (canceled)
12 . A method of screening for an inhibitor of human Nuclear receptor SET Domain containing protein 2 (NSD2), the method comprising the steps of:
(i) measuring kinetic isotope effects on the NSD2-catalyzed methylation of histone H3 lysine 36 to obtain the NSD2 transition state structure,
wherein the NSD2 transition state comprises the structure
(ii) determining the molecular electrostatic potential at the van der Waals surface computed from the wave function of the NSD2 transition state and the geometric atomic volume of the NSD2 transition state;
(iiia) obtaining a chemically stable compound that resembles the molecular electrostatic potential at the van der Waals surface computed from the wave function of the NSD2 transition state and the geometric atomic volume of the NSD2 transition state, or
(iiib) using a computer to design a chemically stable compound that resembles the molecular electrostatic potential at the van der Waals surface computed from the wave function of the NSD2 transition state and the geometric atomic volume of the NSD2 transition state, and synthesizing the compound; and
(iv) testing the compound for inhibitory activity to NSD2 by determining if the compound inhibits NSD2-catalyzed methylation of histone H3 lysine 36,
wherein a compound that inhibits NSD2-catalyzed methylation of histone H3 lysine 36 is an inhibitor of NSD2.
13 . A method of inhibiting NSD2 comprising obtaining a NSD2 inhibitor by the system of claim 1 , and contacting NSD2 with the compound.
14 . A method of treating a subject having a cancer comprising obtaining a NSD2 inhibitor by using the system of claim 1 , and administering the compound to the subject in an amount effective to inhibit NSD2.
15 . The method of claim 14 , wherein the cancer is multiple myeloma, neuroblastoma, glioblastoma, prostate cancer or breast cancer.
16 . The system of claim 1 , wherein the transition state is a S N 2 transition state where a positive charge is distributed between a leaving group, a transferring group and a nucleophile.
17 . The system of claim 1 , wherein the transition state has a C—N distance of 1.8 Å and a C—S distance of 2.6 Å, or the transition state has a C—N distance of 2.10 Å and a C—S distance of 2.53 Å.
18 . (canceled)