Synthesis, biological evaluation and docking studies of trans‐stilbene methylthio derivatives as cytochromes P450 family 1 inhibitors

Abstract

Cytochromes P450 family 1 (CYP1) are responsible for the metabolism of procarcinogens, for example polycyclic aromatic hydrocarbons and aromatic and heterocyclic amines. The inhibition of CYP1 activity is examined in terms of chemoprevention and cancer chemotherapy. We designed and synthesized a series of trans-stilbene derivatives possessing a combination of methoxy and methylthio functional groups attached in different positions to the trans-stilbene skeleton. We determined the effects of synthesized compounds on the activities of human recombinant CYP1A1, CYP1A2 and CYP1B1 and, to explain the variation of inhibitory potency of methoxystilbene derivatives and their methylthio analogues, we employed computational analysis. The compounds were docked to CYP1A1, CYP1A2 and CYP1B1 binding sites with the use of Accelrys Discovery Studio 4.0 by the CDOCKER procedure. For CYP1A2 and CYP1B1, values of scoring functions correlated well with inhibitory potency of stilbene derivatives. All compounds were relatively poor inhibitors of CYP1A2 that possess the most narrow and flat enzyme cavity among CYP1s. For the most active CYP1A1 inhibitor, 2-methoxy-4'-methylthio-trans-stilbene, a high number of molecular interactions was observed, although the interaction energies were not distinctive.

Integrated bioinformatics analysis reveals novel key biomarkers and potential candidate small molecule drugs in gestational diabetes mellitus

“…The binding site sphere radius set at X = 29.50, Y = −31.38 and Z = −38.79 were submitted to the CDOCKER parameter and also calculated binding energy. The X-ray co-crystallized structure and were extracted from Protein Data Bank of PDB code of 4UV7, 5NJX, 3Q4Z and 3FNI of over expressed genes of Epidermal growth factor receptor (EGFR), Heat shock protein 90 alpha family class A member 1 (HSP90AA1), P21 RAC1 activated kinase 1 (PAK1) and Ring-box 1 (RBX1) respectively in gestational diabetes were selected for docking studies [26–29]. The best position was inserted into the molecular area between the protein and the ligand.…”

Structure-Based Drug Design for Cytochrome P450 Family 1 Inhibitors

“…Recently, the CYP1A1 structure was used in studies of interactions of the enzyme with a great number of CYP1A1 substrates and inhibitors summarized in Table 1 , including phytochemicals, for example, dietary flavonoids [ 32 , 41 , 47 ]; drugs, for example, melatonin, debrisoquine, theophylline, clozapine, and carvedilol [ 57 ]; environmental pollutants, for example, aromatic hydrocarbons and their derivatives [ 22 , 28 , 35 , 37 , 45 , 55 ]; and natural and synthetic derivatives of trans -stilbene [ 25 , 46 , 63 ].…”

“…Moreover, CYP1A1 side chains of amino acid residues lining the active site are smaller in comparison to the corresponding residues in CYP1A2. For example, amino acid residues in the vicinity of the heme, Val382 in CYP1A1 and Val395 in CYP1B1, are replaced by the branched Leu382 in CYP1A2 narrowing the CYP1A2 cavity, which results in a lesser affinity of polymethoxystilbenes to CYP1A2 in comparison to CYP1A1 [ 63 ].…”

“…In search of novel CYP1 inhibitors, methylthiostilbene derivatives were designed and synthesized [ 63 , 77 ]. The orientation of a series of polymethoxy- trans -stilbene derivatives containing a 4′-methylthio substituent in the CYP1 active sites was studied, and molecular interactions between ligands and amino acid residues of the enzyme pocket were estimated.…”

“…For this derivative, docked to the CYP1A1 binding site, a high number of nonbonded molecular interactions were observed. However, the binding of 2-methoxy-4′-methylthio- trans -stilbene was not favourable energetically [ 63 ].…”