Investigating the Molecular Basis of N-Substituted 1-Hydroxy-4-Sulfamoyl-2-Naphthoate Compounds Binding to Mcl1

Abstract

Myeloid cell leukemia-1 (Mcl1) is an anti–apoptotic protein that has gained considerable attention due to its overexpression activity prevents cell death. Therefore, a potential inhibitor that specifically targets Mcl1 with higher binding affinity is necessary. Recently, a series of N-substituted 1-hydroxy-4-sulfamoyl-2-naphthoate compounds was reported that targets Mcl1, but its binding mechanism remains unexplored. Here, we attempted to explore the molecular mechanism of binding to Mcl1 using advanced computational approaches: pharmacophore-based 3D-QSAR, docking, and MD simulation. The selected pharmacophore—NNRRR—yielded a statistically significant 3D-QSAR model containing high confidence scores (R2 = 0.9209, Q2 = 0.8459, and RMSE = 0.3473). The contour maps—comprising hydrogen bond donor, hydrophobic, negative ionic and electron withdrawal effects—from our 3D-QSAR model identified the favorable regions crucial for maximum activity. Furthermore, the external validation of the selected model using enrichment and decoys analysis reveals a high predictive power. Also, the screening capacity of the selected model had scores of 0.94, 0.90, and 8.26 from ROC, AUC, and RIE analysis, respectively. The molecular docking of the highly active compound—C40; 4-(N-benzyl-N-(4-(4-chloro-3,5-dimethylphenoxy) phenyl) sulfamoyl)-1-hydroxy-2-naphthoate—predicted the low-energy conformational pose, and the MD simulation revealed crucial details responsible for the molecular mechanism of binding with Mcl1.

Experimental, molecular docking and molecular dynamic studies of natural products targeting overexpressed receptors in breast cancer

“…In the case of the binding site of BCL-W protein consisting of Asp153, Arg160, Val162, Trp167, Val170, Arg171, Arg177, Ala179, and Leu180 residues [ 23 ], the interactions in the hesperidin-BCL-W complex were through two hydrogen interactions with Arg78, one hydrogen interaction with each of Arg56, Thr60, Gly90, and Arg95, one Pi-Cation interaction with Arg56, and one Alkyl interaction with Arg59 ( Fig 1C and 1D ). The binding site residues of MCL-1 protein were determined as His224, Ala227, Phe228, Met231, Leu235, Ile237, Leu246, Val249, Met250, Val253, Phe254, Asp256, Asn260, Arg263, Thr266, Leu267, Phe270, Gly271, Val274, Ile294, and Leu298 [ 24 , 25 ]. According to this, the interacting residues in the hesperidin-MCL-1 complex were Gln189, Arg215, Gly219, Gln221, Arg222, Asn223, Phe273, Lys276, and His320, so that these interactions included seven hydrogen interactions, three Carbon hydrogen interactions, one Amide-Pi Stacked interaction, and three Alkyl and Pi-Alkyl interactions ( Fig 1E and 1F ).…”

Predicted Hotspot Residues Involved in Allosteric Signal Transmission in Pro-Apoptotic Peptide—Mcl1 Complexes

“…Previously, several studies have been carried out on different Bcl-2 family proteins using various MD simulation approaches. These investigations revealed (i) the driving force behind the intra-molecular conformational change [ 58 ], (ii) the helix stability [ 59 , 60 ], (iii) crucial residues involved in heterodimerization [ 61 ] (iv) crucial molecular properties responsible for complexity [ 62 , 63 , 64 ] (v) hot-spot residues [ 65 ] (vi) effects of Bim mutants [ 66 ] and (vii) the inter-helical interactions across families [ 67 ]. Based on this information, we attempted to explore the mMcl1—PAP complexes to extend our understanding of the molecular mechanism of heterodimerization by identifying the key features.…”

Disruption of conserved polar interactions causes a sequential release of Bim mutants from the canonical binding groove of Mcl1

“…In our previous studies, we have carried out a broad range of investigations to understand the molecular mechanism of binding of the Bcl2 family proteins, especially using the MD simulation technique [53][54][55][56][57][58]. These revealed crucial details on (i) intramolecular conformational changes of Bax protein, [53] (ii) the hotspot residues that promote heterodimerization, [55] (iii) the mechanism of small molecule inhibitors binding to Mcl1, [56] and (iv) the molecular properties involved in the complex formation of Mcl1 and small molecular inhibitors [54,57,58]. Based on our previous experience, the current investigation sought to understand the effects of point mutants on the complex stability at the atomistic level using an advanced MD simulation technique, such as SMD.…”