Binding affinities for sulfonamide inhibitors with matrix metalloproteinase‐2 using a linear response method

Abstract

The extracellular matrix (ECM) is a complex structural entity surrounding and supporting cells that are found within mammalian tissues. It is composed of three major classes of biomolecules: (i) structural proteins: collagen and elastin, (ii) specialized proteins: e.g. fibrillin, fibronectin, and laminin, and (iii) proteoglycans.Matrix metalloproteinases (MMPs) are an important class of calcium dependent zinc-containing endopeptidases, involved in the breakdown of ECM, thus playing important roles in growth, remodeling (such as wound healing), and reproduction, among other physiological processes [9]. AbstractDue to their involvement in many pathological conditions, matrix metalloproteinases (MMPs), are very attractive therapeutic targets. Our study focuses on one of them, MMP-2, which is involved in tumor progression and metastasis. Recently, the solution structure of the catalytic domain of MMP-2 complexed with a hydroxamic acid inhibitor (SC-74020) was published by Feng et al. Using the Hanessian group published binding affinity data and the structure published by Feng as a basis, we have built a binding affinity model by targeting the S 2 ' pocket of the enzyme with a set of nine α-N-sulfonylamino hydroxamic acid derivatives. Two binding geometries of each ligand have been generated corresponding to two binding modes denoted A and B, respectively, of which the first one is targeting the S 2 ' pocket and the second one the S 1 pocket. For the binding affinity model developed for mode A the computed activities show a rmsd of 0.583 kcal/mol as compared with the experimental data, and a correlation coefficient r 2 of 0.779, while in the case of the binding mode B a rmsd of 0.834 kcal/mol and correlation coefficient r 2 of 0.500, respectively, were obtained. In conclusion, our data suggest a higher probability for the Phe 76 gated S 2 ' open form pocket to accommodate the substituent α versus the wide solvent exposed S 1 subsite, probability which some research groups could have overlooked due to extensive use in their calculations of non revealing S 2 ' pocket open state crystallographic structures instead of NMR ones.

Towards Predictive Ligand Design With Free-Energy Based Computational Methods?

“…Including Coulombic interactions beyond the sphere of hydration introduces vacuum-like electric fields into the system which are not properly screened by solvent, leading to a number of artefacts [79,124]. Partial pragmatic remedies to these issues may include selective neutralisation of the receptor titratable groups and/or use of continuum models to correct the ∆<V elec_Lig > term for long-range electrostatics [113,123,124,263,279,283,285]. On the other hand, several studies yielded operational LIE models without reported ad hoc adjustment of the system charges [106,107,[286][287][288].…”

“…For the unbound ligand the Coulombic and van der Waals interactions are zero because the solvent is represented by a continuum, while in the bound state these interactions are computed between ligand and receptor. The continuum model can be used in conjunction with MD, MC or hybrid MD/MC (HMC) protocols [112,113], or energy minimization only [113,279,294,297]. A variation is to apply the continuum model after conformational sampling of the ligand-receptor in vacuo, without simulating the free ligand [281].…”

“…Treating γ as a constant has proved effective in a number of studies [94,150,151,283,298]. The term ∆<SASA _Lig > was substituted by a conceptually equivalent cavitation term γ = λ ∆<U Cav > in formulations of the LIE which use a continuum solvent model [112,113,279], where U Cav = c 1 SASA + c 2 and c 1 and c 2 are two empirical coefficients [112].…”

“…Docking against the p38 MAP kinase provided another example where spurious and experimental docking modes were ranked equally well by empirical scores, whilst the MM-PBSA free energy unambiguously favoured the X-ray binding mode [147]. The overall orientation of substituents of metalloproteinase-2 were also investigated with a MM-GB protocol [279], and the most likely binding mode of bornyl caffeate to elastase was suggested based on MM-PBSA calculations [41].…”

Inhibitory effect of acetylsalicylic acid on matrix metalloproteinase - 2 activity in human endothelial cells exposed to high glucose

“…This is not entirely unexpected given a variety of preclinical studies that indicate that MMP inhibitors work effectively in early-stage cancer and not in the terminal ones. Our group is also interested in the in silico study of MMPs -synthetic MMP inhibitors interactions [11].…”