A quantitative structure-activity relationship study on matrix metalloproteinase inhibitors: piperidine sulfonamide aryl hydroxamic acid analogs

A quantitative structure-activity relationship (QSAR) study has been made on a series of piperidine sulfonamide aryl hydroxamic acid analogs acting as matrix metalloproteinase (MMP) inhibitors. The inhibitory potencies of the compounds against two MMPs, MMP-2 and MMP-13, are found to be significantly correlated with the hydrophobic properties of the molecules, suggesting that in both enzymes the hydrophobic interaction is playing a dominant role.     

A quantitative structure-activity relationship study on matrix metalloproteinase inhibitors: Piperidine sulfonamide aryl hydroxamic acid analogs

A quantitative structure-activity relationship (QSAR) study has been made on a series of piperidine sulfonamide aryl hydroxamic acid analogs acting as matrix metalloproteinase (MMP) inhibitors. The inhibitory potencies of the compounds against two MMPs, MMP-2 and MMP-13, are found to be significantly correlated with the hydrophobic properties of the molecules, suggesting that in both enzymes the hydrophobic interaction is playing a dominant role.     

A comparative QSAR study on carbonic anhydrase and matrix metalloproteinase inhibition by sulfonylated amino acid hydroxamates

A quantitative structure-activity relationship (QSAR) study is made on the inhibition of a few isozymes of carbonic anhydrase (CA) and some matrix metalloproteinases (MMPs), both zinc containing families of enzymes, by sulfonylated amino acid hydroxamates. For both enzymes, the inhibition potency of the hydroxamates is found to be well correlated with Kier's first-order valence molecular connectivity index 1chi(v) of the molecule and electrotopological state indices of some atoms. From the results, it is suggested that while hydroxamate-CA binding may involve mostly polar interactions, hydroxamate-MMP and hydroxamate-ChC (ChC: Clostridium histolyticum collagenase, another zinc enzyme related to MMPs) bindings may involve some hydrophobic interactions. Both MMPs and ChC also possess some electronic sites of exactly opposite nature to the corresponding sites in CAs. A group such as C6F5 present in the sulfonyl moiety is shown to be advantageous in both CA and MMP (also ChC) inhibitions, which is supposed to be due to the interaction of this group with Zn2+ ion present in the catalytic site of both families of enzymes.     

A Comparative QSAR Study on Carbonic Anhydrase and Matrix Metalloproteinase Inhibition by Sulfonylated Amino Acid Hydroxamates

A quantitative structure-activity relationship (QSAR) study is made on the inhibition of a few isozymes of carbonic anhydrase (CA) and some matrix metalloproteinases (MMPs), both zinc containing families of enzymes, by sulfonylated amino acid hydroxamates. For both enzymes, the inhibition potency of the hydroxamates is found to be well correlated with Kier's first-order valence molecular connectivity index ¹χ^v of the molecule and electrotopological state indices of some atoms. From the results, it is suggested that while hydroxamate-CA binding may involve mostly polar interactions, hydroxamate-MMP and hydroxamate-ChC (ChC: Clostridium histolyticum collagenase, another zinc enzyme related to MMPs) bindings may involve some hydrophobic interactions. Both MMPs and ChC also possess some electronic sites of exactly opposite nature to the corresponding sites in CAs. A group such as C 6 F 5 present in the sulfonyl moiety is shown to be advantageous in both CA and MMP (also ChC) inhibitions, which is supposed to be due to the interaction of this group with Zn 2+ ion present in the catalytic site of both families of enzymes.     

Quantitative structure-activity relationship study on some 5-lipoxygenase inhibitors

A quantitative structure-activity relationship (QSAR) study has been made on some lipoxygenase inhibitors belonging to the series of omega-phenylalkyl hydroxamic acids, omega-naphthylalkyl hydroxamic acids, eicosatetraenoic acids, and 1H.benzimidazole-4-ols. It was found that the hydrophobic character of the molecules and the size of their substituents selectively govern their lipoxygenase inhibitory activity. The enzyme active site possesses a non-heme ferric ion, a hydrophobic domain, and a carboxylic acid binding site. It was found that while the functional group of inhibitors must interact with the ferric ion, the substituent on one side of it would be involved in hydrophobic interaction and that on the other side in van der Waals interaction with the enzyme so leading to an enhancement in the inhibitory activity of the inhibitors.     

Quantitative Structure-Activity Relationship Study on Some 5-Lipoxygenase Inhibitors

Abstract

A quantitative structure-activity relationship (QSAR) study has been made on some lipoxygenase inhibitors belonging to the series of ω-phenylalkyl hydroxamic acids, ω-naphthylalkyl hydroxamic acids, eicosatetraenoic acids, and 1H.benzimidazole-4-ols. It was found that the hydrophobic character of the molecules and the size of their substituents selectively govern their lipoxygenase inhibitory activity. The enzyme active site possesses a non-heme ferric ion, a hydrophobic domain, and a carboxylic acid binding site. It was found that while the functional group of inhibitors must interact with the ferric ion, the substituent on one side of it would be involved in hydrophobic interaction and that on the other side in van der Waals interaction with the enzyme so leading to an enhancement in the inhibitory activity of the inhibitors.     

QSAR studies on structurally similar 2-(4-methanesulfonylphenyl)pyran-4-ones as selective COX-2 inhibitors: a Hansch approach

QSAR analysis based on classical Hansch approach was adopted on two recently reported novel series of 2-phenylpyran-4-ones as selective cyclooxygenase-2 (COX-2) inhibitors. The 6-methyl derivatives of title compounds bifurcate as 3-phenoxypyran-4-ones (subset A) and 3-phenylpyran-4-ones (subset B) among series 1. Series 2 consists of 5-chloro derivatives of title compounds. Various regression equations were derived to study the influence of phenoxy and phenyl ring substituents of series 1 compounds on COX-2, COX-1 and selective COX-2 over COX-1 inhibitory activity. The best triparametric equation derived for 36 compounds of series 1 explains the hydrophobic, electronic and steric requirements for improved COX-2 inhibitory activity. QSAR model derived to explore the selective COX-2 over COX-1 inhibition showed that selectivity could be influenced by size and lipophilicity of substituents. The size of the first atom of 2 substituents appears to have negative effect on selectivity, whereas highly polar 3 substituents at R are favorable for improved selectivity. QSAR investigations on series 2 compounds revealed some interesting correlation of COX-2 inhibitory activity with calculated physicochemical properties of whole molecules. The positive logP confirms the hydrophobic interaction of series 2 compounds with COX-2 enzyme. The positive MR term indicates that an overall increase in size and polarizabilty of the molecules increases COX-2 inhibitory activity. The positive contribution of structural variable suggests biphenyl analogs are extremely potent COX-2 inhibitors.     

A quantitative structure-activity relationship study of hydroxamate matrix metalloproteinase inhibitors derived from functionalized 4-aminoprolines

A quantitative structure-activity relationship (QSAR) study has been made on the inhibitions of some matrix metalloproteinases (MMPs) by functionalized 4-aminoproline based hydroxamates. Attempts have been made to correlate the inhibition potencies of these hydroxamates with Kier's first-order valence molecular connectivity index ((1)chi(v)) of substituents and electrotopological state (E-state) indices of some atoms. The correlations obtained for the inhibitions of all the enzymes studied, i.e. MMP-1, MMP-2, MMP-3, MMP-7, and MMP-13, were not so uniform, but suggested that in almost all the cases the substituents at the amide nitrogen may be conducive to the activity, though the whole amide group may be sterically unfavourable. Similarly, in most of the cases, the substituens at the phenyl moiety have been found to be beneficial to the inhibition potency and in many cases an electronic role of SO(2) group of the sulfonylphenyl moiety has been indicated.     

In silico QSAR studies of anilinoquinolines as EGFR inhibitors

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.     

Structure-based design of caspase-1 inhibitor containing a diphenyl ether sulfonamide

A series of compounds was designed and prepared as inhibitors of interleukin-1beta converting enzyme (ICE), also known as caspase-1. These inhibitors, which employ a diphenyl ether sulfonamide, were designed to improve potency by forming favorable interactions between the diphenyl ether rings and the prime side hydrophobic region. An X-ray crystal structure of a representative member of the diphenyl ether sulfonamide series bound to the active site of caspase-1 was obtained.     

Inhibition of classical pathway of complement activation with negative charged derivatives of bisphenol A and bisphenol disulphates

In order to obtain strong inhibitors of classical pathway of complement activation the low weight negative charged compounds have been investigated. On the basis of bisphenol A anionic derivatives with one or two carboxylic, sulphate and phosphate groups the critical role of negative charged groups for complement-inhibiting activity has been established. It was determined that two sulphate or phosphate groups in the molecule provide the most inhibiting effect. At the next stage a set of bisphenol disulphates of varying structures has been synthesized and investigated. Bulky hydrophobic groups (cyclohexyliden, fluorenyliden, anthronyliden) at the central part of the bisphenol molecule it was found to increase complement-inhibiting activity markedly. The replacement of the ortho-positions to the charged group by halogens or alkyl groups (allyl, propyl) increases the inhibiting effect. It was showed by ELISA that several compounds studied interact with C1q, C1r /C1s components of complement. For the set of bisphenol disulphates the QSAR equation with hydrophobic coefficient and electronic parameters has been formulated. Both hydrophobic and electrostatic interactions it was established to have a great significance for the inhibition of classical pathway of complement activation.     

A quantitative structure-activity relationship study on some matrix metalloproteinase and collagenase inhibitors

A quantitative structure-activity relationship (QSAR) study is made on some hydroxamic acid-based inhibitors of matrix metalloproteinases (MMPs) and a bacterial collagenase, namely Clostridium histolyticum collagenase (ChC), that also belongs to an MMP family, M-31, using Kier's valence molecular connectivity index (1)chi(v) of the substituents and electrotopological state (E-state) indices of some atoms. The results indicate that out of the four MMPs (MMP-1, MMP-2, MMP-8, and MMP-9) studied, MMP-2 and MMP-9 can be structurally quite similar, but widely differing from MMP-1 and MMP-8 and ChC. For MMP-2 and MMP-9, the inhibition activity of compounds is shown to depend on both (1)chi(v )and E-state indices, while for MMP-1 and MMP-8 it is shown to depend only on E-state indices and for ChC only on (1)chi(v). However, in all the cases, an aromatic group like C(6)F(5) or 3-CF(3)-C(6)H(4) attached to SO(2) moiety in the compounds is indicated to be equally beneficial, due to probably the involvement of fluorine atom(s) in charge-charge interactions with the Zn(2+) ion of the enzymes or in the formation of the hydrogen bonds with some sites of the receptors.     

QSAR of anticancer compounds. Bis(11-oxo-11H-indeno[1,2-b]quinoline-6-carboxamides), bis(phenazine-1-carboxamides), and bis(naphthalimides)

QSAR have been developed for the anticancer activity (growth inhibition) of various tumor cells by bis(11-oxo-11H-indeno[1,2-b]quinoline-6-carboxamides), bis(phenazine-1-carboxamides), and bis(naphthalimides). Of the seven QSAR, positive hydrophobic interactions are found in only two examples: bis(naphthalimides) versus human colon cancer cells. This is consistent with other QSAR of anticancer compounds where hydrophobic interactions are found to be unimportant.     

Carbonic anhydrase inhibitors. N-cyanomethylsulfonamides--a new zinc binding group in the design of inhibitors targeting cytosolic and membrane-anchored isoforms

A series of N-cyanomethyl aromatic sulfonamides and bis-sulfonamides was prepared by reaction of arylsulfonyl halides with aminoacetonitrile. The obtained derivatives incorporated various aryl moieties, such as 4-halogeno/alkyl/aryl/nitro-substituted-phenyl, pentafluorophenyl or 2-naphthyl. Moderate inhibitory activity was detected for some compounds against the cytosolic human isoform II of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), hCA II, with inhibition constants of 90, 180 and 560n M for the 4-nitrophenyl-, 4-iodophenyl- and pentafluorophenyl-N-cyanomethylsulfonamides, respectively. Other derivatives acted as weak inhibitors of isoforms hCA I (KIs of 720 nM-45 microM), hCA II (KIs of 1000-9800 nM) and hCA IX (KIs of 900-10200 nM). Thus, the N-cyanomethylsulfonamide zinc binding group is less effective than the sulfonamide, sulfamate or sulfamide ones for the design of effective CA inhibitors.     

3D QSAR studies on GSK-3 inhibition by aloisines

GSK-3 is involved in various physiological processes and its inhibitors have been evaluated as promising drug candidates for a lot of unmet pathologies. In this paper, inhibition of GSK-3 by aloisines is investigated by 3D QSAR studies. Two alignment rules were applied to check the influence of spatial alignment of the compounds. Both the CoMFA and CoMSIA techniques were carried out and ASS procedure was applied for CoMFA to find a satisfactory model. The best QSAR model obtained is a CoMSIA model characterized with r(2) of 0.938 and q(2) of 0.673 including steric, electrostatic and hydrophobic fields, possessing good predicting ability. To get a better understanding of the relationship between chemical structure and biological activity, a complex structure of aloisine with GSK-3 was obtained by superimposing GSK-3 into the known cocrystal structure of aloisine-CDK2, and then factors that affect the inhibition activity were investigated further, combining the QSAR study with the complex structure, the results of which are in good accordance and complementary to each other.     

Matrix metalloproteinases (MMPs): chemical-biological functions and (Q)SARs

Matrix metalloproteinases (MMPs) are a large family of calcium-dependent zinc-containing endopeptidases, which are responsible for the tissue remodeling and degradation of the extracellular matrix (ECM), including collagens, elastins, gelatin, matrix glycoproteins, and proteoglycan. They are regulated by hormones, growth factors, and cytokines, and are involved in ovarian functions. MMPs are excreted by a variety of connective tissue and pro-inflammatory cells including fibroblasts, osteoblasts, endothelial cells, macrophages, neutrophils, and lymphocytes. These enzymes are expressed as zymogens, which are subsequently processed by other proteolytic enzymes (such as serine proteases, furin, plasmin, and others) to generate the active forms. Matrix metalloproteinases are considered as promising targets for the treatment of cancer due to their strong involvement in malignant pathologies. Clinical/preclinical studies on MMP inhibition in tumor models brought positive results raising the idea that the development of strategies to inhibit MMPs may be proved to be a powerful tool to fight against cancer. However, the presence of an inherent flexibility in the MMP active-site limits dramatically the accurate modeling of MMP-inhibitor complexes. The interest in the application of quantitative structure-activity relationships (QSARs) has steadily increased in recent decades and we hope it may be useful in elucidating the mechanisms of chemical-biological interactions for this enzyme. In the present review, an attempt has been made to explore the in-depth knowledge from the classification of this enzyme to the clinical trials of their inhibitors. A total number of 92 QSAR models (44 published and 48 new formulated QSAR models) have also been presented to understand the chemical-biological interactions. QSAR results on the inhibition of various compound series against MMP-1, -2, -3, -7, -8, -9, -12, -13, and -14 reveal a number of interesting points. The most important of these are hydrophobicity and molar refractivity, which are the most important determinants of the activity.