3D-QSAR Studies on Angiotensin-Converting Enzyme (ACE)Inhibitors: a Molecular Design in Hypertensive Agents

San Juan, Amor A.,Cho, Seung-Joo Korean Chemical Society 2005 Bulletin of the Korean Chemical Society Vol.26 No.6

Angiotensin-converting enzyme (ACE) is known to be primarily responsible for hypertension. Threedimensional quantitative structure-activity relationship (3D-QSAR) models have been constructed using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) for a series of 28 ACE inhibitors. The availability of ACE crystal structure (1UZF) provided the plausible biological orientation of inhibitors to ACE active site (C-domain). Alignment for CoMFA obtained by docking ligands to 1UZF protein using FlexX program showed better statistical model as compared to superposition of corresponding atoms. The statistical parameters indicate reasonable models for both CoMFA ($q^2$ = 0.530, $r^2$ = 0.998) and CoMSIA ($q^2$ = 0.518, $r^2$ = 0.990). The 3D-QSAR analyses provide valuable information for the design of ACE inhibitors with potent activity towards C-domain of ACE. The group substitutions involving the phenyl ring and carbon chain at the propionyl and sulfonyl moieties of captopril are essential for better activity against ACE.

3D-QSAR Study of Competitive Inhibitor for Acethylcholine Esterase (AChE) Nerve Agent Toxicity

San Juan, Amor A.,Cho, Seung-Joo The Korean Society of Toxicogenomics and Toxicopro 2006 Molecular & cellular toxicology Vol.2 No.3

The cholinesterase-inhibiting organophosphorous (OP) compounds known as nerve agents are highly toxic. The principal toxic mechanism of OP compounds is the inhibition of acethylcholine esterase (AChE) by phosphorylation of its catalytic site. The reversible competitive inhibition of AChE may prevent the subsequent OP intoxication. In this study, three-dimensional quantitative structure-activity relationship (3D-QSAR) was performed to investigate the relationship between the 29 compounds with structural diversity and their bioactivities against AChE. In particular, predictive models were constructed using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The results indicate reasonable model for CoMFA ($q^{2}=0.453,\;r^{2}=0.697$) and CoMSIA ($q^{2}=0.518,\;r^{2}=0.696$). The presence of steric and hydophobic group at naphtyl moiety of the model may lead to the design of improved competitive inhibitors for organophosphorous intoxication.

HQSAR Study of Microsomal Prostaglandin E₂ Synthase (mPGES-1) Inhibitors

San Juan, Amor A.,Cho, Seung-Joo,Cho, Hoon Korean Chemical Society 2006 Bulletin of the Korean Chemical Society Vol.27 No.10

Microsomal prostaglandin $E_2$ synthase (mPGES-1) is an enzyme that is associated with inflammation, pain, fever and cancer. Hologram quantitative structure activity relationship (HQSAR) was conducted on the series of MK-886 compounds acting as mPGES-1 inhibitors. A training set with 24 compounds was used to establish the HQSAR model. The best model was chosen based on the cross-validated correlation coefficient ($q^2$=0.884) and the correlation coefficient($r^2$=0.976). The model was utilized to predict the activity of the eight-test set of compounds giving the predictive $r^2$ value of 0.845. The descriptors of the model are based on fragment distinction (atoms, bond and connectivity) and fragment size (2-5 atoms). The atomic contribution maps generated from HQSAR were useful in identifying the important structural features responsible for the inhibitory activity of MK-886 inhibitors. Based on the generated model, the presence of hydrophobic biphenyl group seems to enhance inhibition of mPGES-1 that is in agreement with the previous experiments. In addition, it seems important for a halogen to be substituted to the biphenyl ring and for an acyl group to be attached to the indole moiety for enhanced activity.

HQSAR Study of Microsomal Prostaglandin E2 Synthase (mPGES-1) Inhibitors

Amor A. San Juan,Seung Joo Cho*,Hoon Cho* 대한화학회 2006 Bulletin of the Korean Chemical Society Vol.27 No.10

Microsomal prostaglandin E2 synthase (mPGES-1) is an enzyme that is associated with inflammation, pain, fever and cancer. Hologram quantitative structure activity relationship (HQSAR) was conducted on the series of MK-886 compounds acting as mPGES-1 inhibitors. A training set with 24 compounds was used to establish the HQSAR model. The best model was chosen based on the cross-validated correlation coefficient and the correlation coefficient. The model was utilized to predict the activity of the eight-test set of compounds giving the predictive r2 value of 0.845. The descriptors of the model are based on fragment distinction (atoms, bond and connectivity) and fragment size (2-5 atoms). The atomic contribution maps generated from HQSAR were useful in identifying the important structural features responsible for the inhibitory activity of MK-886 inhibitors. Based on the generated model, the presence of hydrophobic biphenyl group seems to enhance inhibition of mPGES-1 that is in agreement with the previous experiments. In addition, it seems important for a halogen to be substituted to the biphenyl ring and for an acyl group to be attached to the indole moiety for enhanced activity.

HQSAR study of &bgr;-ketoacyl-acyl carrier protein synthase III (FabH) inhibitors

Ashek, Ali,Juan, Amor A. San,Cho, Seung J. Informa Healthcare 2007 Journal of enzyme inhibition and medicinal chemist Vol.22 No.1

<P> The enzyme FabH catalyzes the initial step of fatty acid biosynthesis via a type II fatty acid synthase. The pivotal role of this essential enzyme combined with its unique structural features and ubiquitous occurrence in bacteria has made it an attractive new target for the development of antibacterial and antiparasitic compounds. Predictive hologram quantitative structure activity relationship (HQSAR) model was developed for a series of benzoylamino benzoic acid derivatives acting as FabH inhibitor. The best HQSAR model was generated using atoms and bond types as fragment distinction and 4-7 as fragment size showing cross-validated q2 value of 0.678 and conventional r2 value of 0.920. The predictive ability of the model was validated by an external test set of 6 compounds giving satisfactory predictive r2 value of 0.82. The contribution maps obtained from this model were used to explain the individual atomic contributions to the overall activity. It was confirmed from the contribution map that both ring A and ring C play a vital role for activity. Moreover hydroxyl substitution in the ortho position of ring A is favorable for better inhibitory activity. Therefore the information derived from the contribution map can be used to design potent FabH inhibitors.</P>

3D-QSAR Studies on Angiotensin-Converting Enzyme (ACE) Inhibitors: a Molecular Design in Hypertensive Agents

Seung Joo Cho,Amor A. San Juan 대한화학회 2005 Bulletin of the Korean Chemical Society Vol.26 No.6

Angiotensin-converting enzyme (ACE) is known to be primarily responsible for hypertension. Three-dimensional quantitative structure-activity relationship (3D-QSAR) models have been constructed using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) for a series of 28 ACE inhibitors. The availability of ACE crystal structure (1UZF) provided the plausible biological orientation of inhibitors to ACE active site (C-domain). Alignment for CoMFA obtained by docking ligands to 1UZF protein using FlexX program showed better statistical model as compared to superposition of corresponding atoms. The statistical parameters indicate reasonable models for both CoMFA (q2 = 0.530, r2 = 0.998) and CoMSIA (q2 = 0.518, r2 = 0.990). The 3D-QSAR analyses provide valuable information for the design of ACE inhibitors with potent activity towards C-domain of ACE. The group substitutions involving the phenyl ring and carbon chain at the propionyl and sulfonyl moieties of captopril are essential for better activity against ACE.