Application of the 4D Fingerprint Method with a Robust Scoring Function for Scaffold-Hopping and Drug Repurposing Strategies

Two factors contribute to the inefficiency associated with screening pharmaceutical library collections as a means of identifying new drugs: [1] the limited success of virtual screening (VS) methods in identifying new scaffolds; [2] the limited accuracy of computational methods in predicting off-target effects. We recently introduced a 3D shape-based similarity algorithm of the SABRE program, which encodes a consensus molecular shape pattern of a set of active ligands into a 4D fingerprint descriptor. Here, we report a mathematical model for shape similarity comparisons and ligand database filtering using this 4D fingerprint method and benchmarked the scoring function <i>HWK</i> (Hamza–Wei–Korotkov), using the 81 targets of the DEKOIS database. Subsequently, we applied our combined 4D fingerprint and <i>HWK</i> scoring function VS approach in scaffold-hopping and drug repurposing using the National Cancer Institute (NCI) and Food and Drug Administration (FDA) databases, and we identified new inhibitors with different scaffolds of MycP₁ protease from the mycobacterial ESX-1 secretion system. Experimental evaluation of nine compounds from the NCI database and three from the FDA database displayed IC₅₀ values ranging from 70 to 100 μM against MycP₁ and possessed high structural diversity, which provides departure points for further structure–activity relationship (SAR) optimization. In addition, this study demonstrates that the combination of our 4D fingerprint algorithm and the <i>HWK</i> scoring function may provide a means for identifying repurposed drugs for the treatment of infectious diseases and may be used in the drug-target profile strategy

2′,6′-Dihalostyrylanilines, Pyridines, and Pyrimidines for the Inhibition of the Catalytic Subunit of Methionine S‑Adenosyltransferase‑2

Inhibition of the catalytic subunit of the heterodimeric methionine S-adenosyl transferase-2 (MAT2A) with fluorinated <i>N</i>,<i>N</i>-dialkylaminostilbenes (FIDAS agents) offers a potential avenue for the treatment of liver and colorectal cancers where upregulation of this enzyme occurs. A study of structure–activity relationships led to the identification of the most active compounds as those with (1) either a 2,6-difluorostyryl or 2-chloro-6-fluorostyryl subunit, (2) either an <i>N</i>-methylamino or <i>N</i>,<i>N</i>-dimethylamino group attached in a <i>para</i> orientation relative to the 2,6-dihalostyryl subunit, and (3) either an <i>N</i>-methylaniline or a 2-(<i>N</i>,<i>N</i>-dimethylamino)­pyridine ring. These modifications led to FIDAS agents that were active in the low nanomolar range, that formed water-soluble hydrochloride salts, and that possessed the desired property of not inhibiting the human hERG potassium ion channel at concentrations at which the FIDAS agents inhibit MAT2A. The active FIDAS agents may inhibit cancer cells through alterations of methylation reactions essential for cancer cell survival and growth

Fluorinated <i>N</i>,<i>N</i>‑Dialkylaminostilbenes Repress Colon Cancer by Targeting Methionine <i>S</i>‑Adenosyltransferase 2A

Methionine <i>S</i>-adenosyltransferase 2A (MAT2A) is the catalytic subunit for synthesis of <i>S</i>-adenosylmethionine (SAM), the principal methyl donor in many biological processes. MAT2A is up-regulated in many cancers, including liver cancer and colorectal cancer (CRC) and is a potentially important drug target. We developed a family of fluorinated <i>N</i>,<i>N</i>-dialkylaminostilbene agents, called FIDAS agents, that inhibit the proliferation of CRC cells <i>in vitro</i> and <i>in vivo</i>. Using a biotinylated FIDAS analogue, we identified the catalytic subunit of MAT2A as the direct and exclusive binding target of these FIDAS agents. MAT2B, an associated regulatory subunit of MAT2A, binds indirectly to FIDAS agents through its association with MAT2A. FIDAS agents inhibited MAT2A activity in SAM synthesis, and depletion of MAT2A by shRNAs inhibited CRC cell growth. A novel FIDAS agent delivered orally repressed CRC xenografts in athymic nude mice. These findings suggest that FIDAS analogues targeting MAT2A represent a family of novel and potentially useful agents for cancer treatment