Search results for "molecular model"

Substituted phosphonic analogues of phenylglycine as inhibitors of phenylalanine ammonia lyase from potatoes.

2018

A series of phosphonic acid analogues of phenylglycine variously substituted in phenyl ring have been synthesized and evaluated for their inhibitory activity towards potato l-phenylalanine ammonia lyase. Most of the compounds appeared to act as moderate (micromolar) inhibitors of the enzyme. Analysis of their binding performed using molecular modeling have shown that they might be bound either in active site of the enzyme or in the non-physiologic site. The latter one is located in adjoining deep site nearby the to the entrance channel for substrate into active site.

Theoretical study of the temperature dependence of dynamic effects in thymidylate synthase.

2010

A theoretical study of the temperature dependence of dynamic effects in the rate limiting step of the reaction catalyzed by thymidylate synthase is presented in this paper. From hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) optimizations of transition state structures within a fully flexible molecular model, free downhill molecular dynamics trajectories have been performed at four different temperatures. The analysis of the reactive and non-reactive trajectories in the enzyme environment has allowed us to study the geometric and electronic coupling between the substrate, the cofactor and the protein. The results show how the contribution of dynamic effects to the rate enhancement mea…

Synthesis and Structural Model of an α(2,6)-Sialyl-T Glycosylated MUC1 Eicosapeptide under Physiological Conditions

2006

To study the effect of O-glycosylation on the conformational propensities of a peptide backbone, a 20-residue peptide (GSTAPPAHGVTSAPDTRPAP) representing the full length tandem repeat sequence of the human mucin MUC1 and its analogue glycosylated with the (2,6)-sialyl-T antigen on Thr11, were prepared and investigated by NMR and molecular modeling. The peptides contain both the GVTSAP sequence, which is an effective substrate for GalNAc transferases, and the PDTRP fragment, a known epitope recognized by several anti-MUC1 monoclonal antibodies. It has been shown that glycosylation of threonine in the GVTSAP sequence is a prerequisite for subsequent glycosylation of the serine at GVTSAP. Furt…

Toward engineering efficient peptidomimetics. Screening conformational landscape of two modified dehydroaminoacids

2013

Effective peptidomimetics should posses structural rigidity and appropriate interaction pattern leading to potential spatial and electronic matching to the target receptor site. Rational design of such small bioactive molecules could push chemical synthesis and molecular modeling toward faster progress in medicinal chemistry. Conformational properties of N-t-butoxycarbonyl-glycine-(E/Z)-dehydrophenylalanine N′,N′-dimethylamides (Boc-Gly-(E/Z)-ΔPhe-NMe2) in chloroform were studied by NMR and IR spectroscopy. The experimental findings were supported by extensive calculations at DFT(B3LYP, M06-2X) and MP2 levels of theory and the β-turn tendency for both isomers of the studied dipeptide were d…

Development and optimisation of computational tools for drug discovery

The aim of my PhD project was the development, optimisation, and implementation of new in silico virtual screening protocols. Specifically, this thesis manuscript is divided into three main parts, presenting some of the papers published during my doctoral work. The first one, here named CHEMOMETRIC PROTOCOLS IN DRUG DISCOVERY, is about the optimisation and application of an in house developed chemometric protocol. This part has been entirely developed at the University of Palermo - STEBICEF Department - under the guide of my supervisors. During the development of this part I have personally worked on the tuning and optimisation of the algorithm and on the docking campaigns to obtain molecul…

Suitability ofMMGBSAfor the selection of correct ligand binding modes from docking results

2018

The estimation of the correct binding mode and affinity of a ligand into a target protein using computational methods is challenging. However, docking can introduce poses from which the correct binding mode could be identified using other methods. Here, we analyzed the reliability of binding energy estimation using the molecular mechanics-generalized Born surface area (MMGBSA) method without and with energy minimization to identify the likely ligand binding modes within docking results. MMGBSA workflow (a) outperformed docking in recognizing the correct binding modes of androgen receptor ligands and (b) improved the correlation coefficient of computational and experimental results of rescor…

Phosphonic Analogues of Phenylglycine as Inhibitors of Aminopeptidases: Comparison of Porcine Aminopeptidase N, Bovine Leucine Aminopeptidase and Ami…

2019

Inhibitory activity of 14 phosphonic analogues of phenylglycine, substituted in aromatic ring by fluorine and chlorine, was determined towards porcine aminopeptidase N. The obtained data served as a basis for studying their interaction with the enzyme as modelled by the use of Schrödinger Release 2018 program. The observed linearity between modelled Gibbs free energy differences and inhibitory constants indicated the usefulness of this program. The obtained binding mode was compared with this modelled for bovine lens leucine aminopeptidase. Although both enzymes differ in the number of zinc ions present in the active site, they are considered to exhibit similar activity towards sub…

Cooperative Effects Enhance Electric-Field-Induced Conductance Switching in Molecular Monolayers

2011

The anchoring of molecules with functional groups at surfaces permits information processing based on two stable molecular states that can be tuned externally by light irradiation and external fields. By using a molecular model that incorporates the essential characteristics of the problem, we show that the local interactions between adjacent molecules in a densely packed monolayer can stabilize domains with the same molecular state because of cooperative processes, enhancing significantly the switching properties between the molecular states. The case of electric-field-induced conductance switching is exploited in two possible applications: the design of a logic gates system and the operat…

Diels-Alder-Reaktionen von Vinylindolen mit Arin und 1,4-Benzochinonen: Neue potentielle DNA-Interkalatoren

1991

Diels-Alder reactions of 2- and 3-vinylindoles with aryne, 1,4-benzo- and 1,4-naphtho-quinone lead to new six-ring annellated carbazoles. Molecular modeling studies predict that the compounds with coplanar framework are able to intercalate with the B-DNA.

Simple molecular model for the binding of antibiotic molecules to bacterial ion channels

2003

A molecular model aimed at explaining recent experimental data by Nestorovich et al. [Proc. Natl. Acad. Sci. USA 99, 9789 (2002)] on the interaction of ampicillin molecules with the constriction zone in a channel of the general bacterial porin, OmpF (outer membrane protein F), is presented. The model extends T. L. Hill’s theory for intermolecular interactions in a pair of binding sites [J. Am. Chem. Soc. 78, 3330 (1956)] by incorporating two binding ions and two pairs of interacting sites. The results provide new physical insights on the role of the complementary pattern of the charge distributions in the ampicillin molecule and the narrowest part of the channel pore. Charge matching of int…