Docking and Quantum Mechanics-Guided CoMFA Analysis of b-RAF Inhibitors

Muddassar, M.,Pasha, F. A.,Yoo, Kyung-Ho,Lee, So-Ha,Cho, Seung-Joo Korean Chemical Society 2008 Bulletin of the Korean Chemical Society Vol.29 No.8

Pyrazine derivatives bind to b-RAF receptor which is important in cancer therapy. The ligand-receptor interactions have been studied by comparative molecular field analysis (CoMFA) and molecular docking methods. Applying conventional ligand-based alignment schemes for the whole set was not successful. However, QM and DFT results suggested that some ligands have electrostatic interaction while others have steric interactions. On the basis of these results, we divided the dataset into two subsets. Electrostatic effect was found to be important in one set while steric effect for the other. Best docking modes were obtained for each subset based on the available crystal structure. These receptor-guided CoMFA models propose an interesting possibility which is difficult to obtain otherwise. i.e., in one binding mode the electrostatic interaction plays a key role for one subset ($q^2$ = 0.46, $r^2$ = 0.98), while in another binding mode steric effect is important with another subset ($q^2$ = 0.43, $r^2$ = 0.74).

Elucidation of binding mode and three dimensional quantitative structure-activity relationship studies of a novel series of protein kinase B/Akt inhibitors.

Muddassar, M,Pasha, F A,Neaz, M M,Saleem, Y,Cho, S J Springer 2009 Journal of molecular modeling Vol.15 No.2

<P>Protein kinase B (PKB; also known as Akt kinase) is located downstream in the PI-3 kinase pathway. Overexpression and constitutive activation of PKB/Akt leads to human prostate, breast and ovarian carcinomas. A series of 69 PKB/Akt inhibitors were examined to explore their binding modes using FlexX, and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies based on comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed to provide structural insights into these compounds. CoMFA produced statistically significant results, with cross-validated q ( 2 ) and non-cross validated correlation r(2) coefficients of 0.53 and 0.95, respectively. For CoMSIA, steric, hydrophobic and hydrogen bond acceptor fields jointly yielded 'leave one out' q(2) = 0.51 and r(2) = 0.84. The predictive power of CoMFA and CoMSIA was determined using a test set of 13 molecules, which gave correlation coefficients, r(2)(predictive) of 0.58 and 0.62, respectively. Molecular docking revealed that the binding modes of these molecules in the ATP binding sites of the Akt kinase domain were very similar to those of the co-crystallized ligand. The information obtained from 3D contour maps will allow the design of more potent and selective Akt kinase inhibitors.</P>

Receptor Guided 3D-QSAR: A Useful Approach for Designing of IGF-1R Inhibitors

Muddassar, M.,Pasha, F. A.,Chung, H. W.,Yoo, K. H.,Oh, C. H.,Cho, S. J. Hindawi Publishing Corporation 2008 Journal of biomedicine & biotechnology Vol.2008 No.-

<P>Research by other investigators has established that insulin-like growth factor‐1 receptor (IGF-1R) is a key oncological target, and that derivatives of 1, 3-disubstituted-imidazo[1,5-<I>α</I>] pyrazine are potent IGF-1R inhibitors. In this paper, we report on our three-dimensional quantitative structure activity relationship (3D-QSAR) studies for this series of compounds. We validated the 3D-QSAR models by the comparison of two major alignment schemes, namely, ligand-based (LB) and receptor-guided (RG) alignment schemes. The latter scheme yielded better 3D-QSAR models for both comparative molecular field analysis (CoMFA) (<I>q</I><SUP>2</SUP> = 0.35, <I>r</I><SUP>2</SUP> = 0.95) and comparative molecular similarity indices analysis (CoMSIA) (<I>q</I><SUP>2</SUP> = 0.51, <I>r</I><SUP>2</SUP> = 0.86). We submit that this might arise from the more accurate inhibitor alignment that results from using the structural information of the active site. We conclude that the receptor-guided 3D-QSAR may be helpful to design more potent IGF-1R inhibitors, as well as to understand their binding affinity with the receptor.</P>

Docking and Quantum Mechanics-Guided CoMFA Analysis of b-RAF Inhibitors

조승주,M. Muddassar,F. A. Pasha,유경호,이소하 대한화학회 2008 Bulletin of the Korean Chemical Society Vol.29 No.8

Pyrazine derivatives bind to b-RAF receptor which is important in cancer therapy. The ligand-receptor interactions have been studied by comparative molecular field analysis (CoMFA) and molecular docking methods. Applying conventional ligand-based alignment schemes for the whole set was not successful. However, QM and DFT results suggested that some ligands have electrostatic interaction while others have steric interactions. On the basis of these results, we divided the dataset into two subsets. Electrostatic effect was found to be important in one set while steric effect for the other. Best docking modes were obtained for each subset based on the available crystal structure. These receptor-guided CoMFA models propose an interesting possibility which is difficult to obtain otherwise. i.e., in one binding mode the electrostatic interaction plays a key role for one subset (q2 = 0.46, r2 = 0.98), while in another binding mode steric effect is important with another subset (q2 = 0.43, r2 = 0.74).

QM and Pharmacophore based 3D-QSAR of MK886 Analogues against mPGES-1

Pasha, F.A.,Muddassar, M.,Jung, Hwan-Won,Yang, Beom-Seok,Lee, Cheol-Ju,Oh, Jung-Soo,Cho, Seung-Joo,Cho, Hoon Korean Chemical Society 2008 Bulletin of the Korean Chemical Society Vol.29 No.3

Microsomal prostaglandin E2 synthase (mPGES-1) is a potent target for pain and inflammation. Various QSAR (quantitative structure activity relationship) analyses used to understand the factors affecting inhibitory potency for a series of MK886 analogues. We derived four QSAR models utilizing various quantum mechanical (QM) descriptors. These QM models indicate that steric, electrostatic and hydrophobic interaction can be important factors. Common pharmacophore hypotheses (CPHs) also have studied. The QSAR model derived by best-fitted CPHs considering hydrophobic, negative group and ring effect gave a reasonable result (q2 = 0.77, r2 = 0.97 and Rtestset = 0.90). The pharmacophore-derived molecular alignment subsequently used for 3D-QSAR. The CoMFA (Comparative Molecular Field Analysis) and CoMSIA (Comparative Molecular Similarity Indices Analysis) techniques employed on same series of mPGES-1 inhibitors which gives a statistically reasonable result (CoMFA; q2 = 0.90, r2 = 0.99. CoMSIA; q2 = 0.93, r2 = 1.00). All modeling results (QM-based QSAR, pharmacophore modeling and 3D-QSAR) imply steric, electrostatic and hydrophobic contribution to the inhibitory activity. CoMFA and CoMSIA models suggest the introduction of bulky group around ring B may enhance the inhibitory activity.

Pharmacophore Identification and Validation Study of CK2 Inhibitors Using CoMFA/CoMSIA

Morshed, Mohammad Neaz,Muddassar, Muhammad,Pasha, Farhan Ahmad,Cho, Seung Joo Blackwell Publishing Ltd 2009 Chemical biology & drug design Vol.74 No.2

<P>Protein kinase CK2, also known as casein kinase-2, has been found to be involved in cell growth, proliferation and suppression of apoptosis, which is related to human cancers. The series of compounds were identified as casein kinase-2 inhibitors and their inhibitory activities are a function of a variation of their structures. The current study deals with the pharmacophore identification and, accordingly, the three-dimensional quantitative structure–activity relationship model development using Pharmacophore Alignment and Scoring Engine. Several hypotheses were developed for the molecular alignments. On the basis of statistical values, the best-fitted model was identified and the same alignment was used for 3D-QSAR using comparative molecular field analysis/comparative molecular similarity index analysis. Both the CoMFA (<I>R</I> <SUP>2</SUP><SUB>CV</SUB><I> </I>= 0.58, <I>R</I> <SUP>2</SUP> = 0.82 and <I>r</I> <SUP>2</SUP><SUB>pred</SUB> = 0.62) and the comparative molecular similarity index analysis (<I>R</I> <SUP>2</SUP><SUB>CV</SUB> = 0.74, <I>R</I> <SUP>2</SUP><I> </I>= 0.98 and <I>r</I> <SUP>2</SUP><SUB>pred</SUB> = 0.81) gave reasonable results. Besides pharmacophore-based alignment, the maximum common substructure-based alignment was also used for the comparative molecular field analysis and comparative molecular similarity index analysis. The pharmacophore-based alignment was more prominent and it has provided important information for the modelling of potent inhibitors. The overall study implies that a highly positive and bulky group with H-bond donating property is desirable around the nitrogen atom adjacent to the pyrrolidine ring.</P>

Molecular Docking and 3D QSAR Studies of Chk2 Inhibitors

Pasha, Fahran Ahmad,Muddassar, Muhammad,Joo Cho, Seung Blackwell Publishing Ltd 2009 Chemical biology & drug design Vol.73 No.3

<P>Isothiazole-carboxamidines are potent ATP competitive checkpoint kinases (Chk2) inhibitors. Three-dimensional quantitative structure–activity relationship models were developed using comparative molecular field analysis and comparative molecular similarity indices analysis. The study was performed using three different geometrical methods. In geometrical method-1, molecules were fully optimized by PM3 Hamiltonian and aligned using common substructure. This alignment was subsequently used for Ligand-based comparative molecular field analysis and comparative molecular similarity indices analysis. In receptor-guided analyses, the receptor coordinates were obtained from public domine (PDB 2cn8). The molecule-7 was docked into receptor protein using FlexX and two plausible binding modes were identified. These modes were used as templates for geometrical method-2 and 3. These methods were used for 3D QSAR. The geometrical method-3-based comparative molecular field analysis (<I>q</I><SUP> 2</SUP> = 0.75, <I>r</I><SUP> <I>2</I></SUP> = 0.87 and <I>r </I><SUP><I>2</I></SUP><SUB>predict</SUB> = 0.81) and comparative molecular similarity indices analysis (<I>q </I><SUP><I>2</I></SUP> = 0.90, <I>r</I><SUP> <I>2</I></SUP> = 0.96 and <I>r</I><SUP> <I>2</I></SUP><SUB>predict</SUB> = 0.75) gave better result. The steric, hydrophobic and hydrogen bond donor fields effects significantly contribute to activity. In this way, the receptor-guided study presents a more detailed understanding about chk2 active site interactions. The study indicated some modifications to the active molecule which might be valuable to improve the activity.</P>

Mechanism based QSAR studies of N-phenylbenzamides as antimicrobial agents

Pasha, F.A.,Muddassar, M.,Lee, C.,Cho, S.J. Elsevier Science B.V 2008 Environmental toxicology and pharmacology Vol.26 No.2

N-Phenyl benzamides are potent antibacterial agents. They are active against both Gram-positive and Gram-negative bacteria. The Gram-positive bacteria have strong and thick cell wall while the Gram-negative bacterial have thin and permeable cell wall. The DFT based QSAR reveals that molecular weight and total energy significantly contribute to activity against both kinds of target. The electrophilicity index involved in QSAR models derived with anti-Gram-positive activity indicates the dominance of electrostatic interaction. The molar refractivity and logP is involved in QSAR model derived with anti-Gram-negative activity shows steric and hydrophobic interaction. The CoMFA and CoMSIA results also indicate that anti-Gram-positive bacterial activity is a function of electrostatic field effect but the anti-Gram-negative activity depends on hydrophobicity and steric field effect. The CoMFA and CoMSIA contour maps give an indication, the electropositive group around benzene ''X'' and an electronegative group around carbonyl oxygen is desirable for better anti-Gram-positive bacterial activity. A hydrophobic group around meta position of ring ''X'' with bulky group at ortho position and a small group at para position are desirable for better activity against Gram-negative target. The findings are reasonable and the mechanism might be different due to difference in composition of cell wall. The cell wall of Gram-positive target does not allow the permeability and only external electrostatic interaction is possible while the cell wall of Gram-negative target allows the permeability of molecules inside the cell for possible hydrophobic and steric bulk interaction.

In silico QSAR studies of anilinoquinolines as EGFR inhibitors.

Pasha, Farhan Ahmad,Muddassar, Muhammad,Srivastava, Anil Kumar,Cho, Seung Joo Springer 2010 JOURNAL OF MOLECULAR MODELING Vol.16 No.2

<P>Members of the epidermal growth factor receptor (EGFR) family of proteins are frequently overactive in solid tumors. A relatively new therapeutic approach to inhibit the kinase activity is the use of ATP-competitive small molecules. In silico techniques were employed to identify the key interactions between inhibitors and their protein receptors. A series of EGFR inhibitory anilinoquinolines was studied within the framework of hologram quantitative structure activity relationship (HQSAR), density functional theory (DFT)-based QSAR, and three-dimensional (3D) QSAR (CoMFA/CoMSIA). The HQSAR analysis implied that substitutions at certain sites on the inhibitors play an important role in EGFR inhibition. DFT-based QSAR results suggested that steric and electronic interactions contributed significantly to the activity. Ligand-based 3D-QSAR and receptor-guided 3D-QSAR analyses such as CoMFA and CoMSIA techniques were carried out, and the results corroborated the previous two approaches. The 3D QSAR models indicated that steric and hydrophobic interactions are dominant, and that substitution patterns are an important factor in determining activity. Molecular docking was helpful in identifying a bioactive conformer as well as a plausible binding mode. The docked geometry-based CoMFA model with steric and electrostatic fields effect gave q(2) = 0.66, r(2) = 0.94 with r(2) (predictive) = 0.72. Similarly, CoMSIA with hydrophobic field gave q(2) = 0.59, r(2) = 0.85 with r(2) (predictive) = 0.63. Bulky groups around site 3 of ring 'C', and hydrophilic and bulky groups at position 6 of ring 'A' are desirable, with a hydrophobic and electron-donating group at site 7 of ring 'A' being helpful. Accordingly, potential EGFR inhibitors may be designed by modification of known inhibitors.</P>

DFT‐based <i>de novo</i> QSAR of Phenoloxidase Inhibitors

Pasha, Farhan Ahmad,Muddassar, Muhhammad,Beg, Yakub,Cho, Seung Joo Blackwell Publishing Ltd 2008 Chemical biology & drug design Vol.71 No.5

<P>The phenoloxidase or tyrosinase is a key enzyme in insects, which is responsible for hydroxylation of tyrosine into <I>o</I>‐quinones via <I>o</I>‐diphenols. A series of benzaldehyde thiosemicarbazone, benzaldehyde and benzoic acid families were taken with their pragmatic pIC<SUB>50</SUB> values against phenoloxidase from pieris rapae (Lepidoptera) larvae. Density functional theory‐based quantitative structure–activity relationship (QSAR) analyses were performed to speculate the key interaction. The most fitted four different QSAR models were identified and discussed. The softness, electrophilicity index, molar refractivity and log <I>P</I> were identified as best descriptors; however, the atomic values of softness and philicity obtained from Fukui function are more significant than global values. The study reveals that electrostatic and steric fields jointly contribute to activity. To gain further insight, the three‐dimensional quantitative structure–activity relationship (3D‐QSAR) analyses were performed using two molecular field techniques: comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The successful 3D‐QSAR models were obtained from CoMFA (<I>q</I><SUP>2<I> </I></SUP>= 0.94, <I>r</I><SUP>2<I> </I></SUP>= 0.99, <SUP><I> </I></SUP>= 0.92) and CoMSIA (<I>q</I><SUP>2<I> </I></SUP>= 0.94, <I>r</I><SUP>2<I> </I></SUP>= 0.98, = 0/95). The CoMFA and CoMSIA results indicate that, a bulky and negative group around sulfur atom but a small and positive group around nitrogen atom might have good effects on activity. The <I>ortho</I> and <I>meta</I> positions of ring are favorable for small group. These QSAR models might be helpful to design the novel and potent inhibitors.</P>