The predicted inhibition constant (Ki) and the predicted inhibitor concentration (IC90) of the HIV‐1 protease (HIV‐1 PR) inhibitors: symmetric and nonsymmetric ‐ benzyl, ketone, oxime, pyrazole, imidazole, and triazole cyclic urea derivatives, were obtained by the 3D‐CoMFA (Comparative Molecular Field Analysis) method. The CoMFA statistical parameters: cross‐validate correlation coefficient (q2), higher than 0.5, and the fitted correlation coefficient (r2), higher than 0.90 validated the predicted biological activities. The best predictions were found for the trifluoromethyl ketoxime derivative (log 1/Ki predict = 8.42), the m‐pyridineCH2 pyrazole derivative (log 1/Ki predict = 9.77) and the 1,2,3 triazole derivative (log 1/Ki predict = 7.03). We attempted to design a new potent HIV‐1 protease inhibitor by addition of o‐benzyl to the (p‐HOPhCH2) pyrazole 12f derivative inhibitor. A favorable steric area surrounded the o‐benzyl, suggesting a possible new potent HIV‐1 protease inhibitor.

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.