The effects of ligand charge, orientation and size on the binding of potential inhibitors for aldehyde dehydrogenase

Abstract

L-DOPA, used as a therapy for patients with Parkinson's disease, is transformed into needed dopamine in the brain. This dopamine can then be deactivated via metabolism by a series of enzymes, including aldehyde dehydrogenase (ALDH). The targeted inhibition of the ALDH enzyme may help to prolong L-DOPA therapy. A series of potential inhibitors has been studied via ab initio models using a crystalstructure of the ALDH enzyme with an inhibitor bound in its active site (PDB ID: 4WP7). The positions of novel dopaminergic derivatives were optimized in the active site using M062X/6-31G with implicit solvation and relaxed amino-acid side-chains. This work examines different single molecule orientations, as well as double molecule configurations. Various sizes of ligands were also studied. Interaction energies between the ligands and the protein were calculated using M062X with the 6-311+G* basis set. Some potential inhibitors show promising results such as the MP and CAM series.

Investigating Paracetamol’s Role as a Potential Treatment for Parkinson’s Disease: Ab Initio Analysis of Dopamine, l-DOPA, Paracetamol, and NAPQI Interactions with Enzymes Involved in Dopamine Metabolism

“…Paracetamol, NAPQI, dopamine, and l -DOPA were studied in all eight active sites, while the rest of the ligands were studied only in those enzymes for which they are a natural substrate (Figure ). The isolation and preparation of active sites for ALDH, PheOH, TyrOH, sulfotransferase (SULT1A3), and catechol- o -methyltransferase (COMT) have been described in our previous work. ,− In short, the crystal structures of each enzyme with a bound catecholic or near-catecholic ligand were identified and downloaded from the protein databank. The active site for the catecholic ligand in the crystal structure was chosen for this study.…”

“…The isolation and preparation of active sites for ALDH, 14 PheOH, 15 TyrOH, 16 sulfotransferase (SULT1A3), 17 and catechol- o -methyltransferase (COMT) 18 have been described in our previous work. 13 , 19 − 22 In short, the crystal structures of each enzyme with a bound catecholic or near-catecholic ligand were identified and downloaded from the protein databank. The active site for the catecholic ligand in the crystal structure was chosen for this study.…”

“…For DDC, 25 the active site included phe579, phe309, phe80, ile577, trp71, lys303, his192, his302, pro81, thr82, thr246, tyr79, and the cofactor pyridoxal phosphate (PLP). The previously studied active sites contained the following residues: Ala462, Cys302, Gly125, Gly294, Gly458, His293, Ile304, Phe171, Ser461, Thr129, Trp178, Tyr297, Val174, and Val460 (ALDH); 22 Arg270, Glu280, Glu330, Gly346, His285, Phe331, Pro279, Pro281, Ser349, Ser350, Thr278, Trp326, Tyr138, and Tyr277 (PheOH); 21 Fe501, Val291, Gly293, Leu294, Leu295, Ser296, Phe300, Leu301, Thr312, Tyr314, Arg316, Glu326, Pro327, His331, Glu332, Tyr336, Tyr371, Trp372, Glu376, Phe377, Gly392, Ser395, and Ser396 (TyrOH); 20 Lys106, His108, His149, Glu146, Asp86, Ala148, Phe24, Phe81, Phe142, and Pro47 (SULT); 19 and Mg, Asp169, Asn170, Asp141, Glu199, Trp38, Met40, Val42, Pro174, Trp253, Val388, Leu413, and Pro174 (COMT). 13 In all cases, amino acid residues were capped with –H or –OH to maintain the charge found in the full protein structure.…”

Ab Initio and DFT Investigation of Effect of Substituent at the C7 Position of 4 Amino Sialidase Inhibitor

“…It is clear from table 2 that guanidino is the only substituent that attains higher binding affinity among all the seven substituents taken into account for the analysis. Guanidino substituent contains two polarizable amino groups in its structure and this polarization accounts for higher binding affinity 23 . The electronic charge transfer between substrate and receptor also favors high binding affinity.…”