Lead identification and optimization of novel collagenase inhibitors; pharmacophore and structure based studies

Kalva, Sukesh; Vadivelan, S.; Sanam, Ramadevi; Jagarlapudi, Sarma A.R.P.; Saleena, Lilly M.

doi:10.6026/97320630008301

Cited by 8 publications

(2 citation statements)

References 20 publications

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“…The S1′ loop region for MMP‐13 is located at residues 244–255. The size and amino acid residues of the S1′ loop in MMP‐13 differ from other MMPs . The long loop size of MMP‐13 that can accommodate large P1′ groups has been suggested to be a determining factor for the selective binding of inhibitors of MMP‐13 .…”

Section: Introductionmentioning

confidence: 99%

Recent Research Advances in Selective Matrix Metalloproteinase‐13 Inhibitors as Anti‐Osteoarthritis Agents

2017

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Matrix metalloproteinase-13 (MMP-13) plays a key role in the degradation of type II collagen in cartilage and bone in osteoarthritis (OA). The subtle differences between the S1' loop of MMP-13 and that of other MMPs offer a structural base for the design of selective MMP-13 inhibitors to mitigate the unperceived risk associated with inhibiting other MMP isoforms. In this review, we summarize zinc-binding and non-zinc-binding selective MMP-13 inhibitors. The zinc-binding MMP-13 inhibitors contain a small set of zinc-binding groups (ZBGs), including hydroxamic acid, pyrimidinetrione, reversed hydroxamic acid and hydantoin, carboxylic acid, 1,2,4,-triazole, and 1,2,4,-triazolone. The non-zinc-binding MMP-13 inhibitors have different structural scaffolds, including diphenyl ethers, biaryls (aryltetrazoliums, arylfurans, pyrazole-indoles), pyrimidines, and aryl/cycloalkyl-fused pyrimidines. This review provides a systematic overview of recent developments in MMP-13 inhibitors for the treatment of OA, with emphasis on their enzyme inhibitory potency, selectivity, and biological activities, and highlights the various binding modes of typical inhibitors with MMP-13.

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Section: Introductionmentioning

confidence: 99%

Recent Research Advances in Selective Matrix Metalloproteinase‐13 Inhibitors as Anti‐Osteoarthritis Agents

2017

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“…Pharmacophore mapping can be used in designing the inhibitors in several ways, including justification of activity trends in molecules, searching of databases to find new chemical entities, and to identify important features for activity. 17…”

Section: Introductionmentioning

confidence: 99%

Prediction of MMP-9 inhibitory activity of N-hydroxy-α-phenylsulfonylacetamide derivatives by pharmacophore based modeling and 3-D QSAR studies

Rathee

Lather²,

Dureja

2018

Porto Biomedical Journal

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Matrix metalloproteinase-9 (MMP-9), also known as gelatinase B, is a MMP that is strongly associated with multiple cellular processes including proliferation, angiogenesis, and metastasis. Various studies have shown that N-hydroxy-α-phenylsulfonylacetamide (HPSAs) derivatives are promising and selective for the MMP-9 inhibition. In the present study, we have selected and reported 80 HPSAs derivatives as inhibitors of MMP-9 and performed structure-based 3-dimensional quantitative structure–activity relationship (3D-QSAR) studies to elucidate the important structural elements responsible for binding affinity. Developed pharmacophore models; QSAR model I contains 2 hydrogen-bond acceptors (A), 2 hydrogen-bond donors (D), and 1 aromatic ring (R) and QSAR model II contains 3 hydrogen-bond acceptors (A), 1 positive ionic (P), and 1 aromatic ring (R). The statistical results of QSAR models (I and II) such as good correlation coefficient (0.61 for I and 0.63 for II), good predictive power (0.84 and 0.77 for I and II, respectively) with low standard deviation (SD\0.3 for both) strongly suggest that the developed models are virtuous for the future prediction of MMP-9 inhibitory activity of HPSAs derivatives. The geometry and features of pharmacophore were expected to be useful for further design and development of selective MMP-9 inhibitors.

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Combined structure- and ligand-based pharmacophore modeling and molecular dynamics simulation studies to identify selective inhibitors of MMP-8

2014

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Matrix metalloproteinase-8 (MMP-8) is the key mediator in initiating type I collagen degradation and is associated with rheumatoid arthritis. In the present study, a pharmacophore hypothesis was developed based on selective non zinc binding inhibitors of MMP-8. The pharmacophore hypothesis was refined manually and validated by observing structures and the interactions of MMP-8 inhibitors. The refined pharmacophore model was able to discriminate the non-zinc binding inhibitors of MMP-8 with respect to other inhibitors. Hence this study proposes a combined structure- and ligand-based pharmacophore model that is suitable for retrieving the novel inhibitors of MMP-8. The pharmacophore hypothesis AADRH was used as query for retrieving potential compounds from the Zinc database and hits were selected based on the catalytic selective amino acid residues of Arg 222, and Tyr 227. We identified six compounds as potent inhibitors and their selectivity profile were checked against different subtypes of MMPs using the cross-docking method. Molecular dynamics results indicated that ZINC 00673680 forms a stable interaction with the key amino acid residues and avoids the zinc atom with a distance of 5.49 Å. Our computational study might be useful for further development of selective MMP-8 inhibitors.

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Lead identification and optimization of novel collagenase inhibitors; pharmacophore and structure based studies

Cited by 8 publications

References 20 publications

Recent Research Advances in Selective Matrix Metalloproteinase‐13 Inhibitors as Anti‐Osteoarthritis Agents

Recent Research Advances in Selective Matrix Metalloproteinase‐13 Inhibitors as Anti‐Osteoarthritis Agents

Prediction of MMP-9 inhibitory activity of N-hydroxy-α-phenylsulfonylacetamide derivatives by pharmacophore based modeling and 3-D QSAR studies

Combined structure- and ligand-based pharmacophore modeling and molecular dynamics simulation studies to identify selective inhibitors of MMP-8

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