Abstract
Fragment-Based Drug Discovery (FBDD) approaches have gained popularitynot only in industry but also in academic research institutes. However, the computational prediction of the binding mode adopted by fragment-like molecules within a protein binding site is still a very challenging task. One of the most crucial aspects of fragment binding is related to the large amounts of bound waters in the targeted binding pocket. The binding affinity of fragmentsmay not be sufficientto displace the bound water molecules. In the present work, we confirmed the importance of the bound water molecules in the correct prediction of the fragment binding mode. Moreover, we investigate whether the use of methods based on explicit solvent molecular dynamics simulations can improve the accuracy of fragment posing. The protein chosen for this study is HSP-90.
Highlights
Fragment-Based Drug Discovery [1] (FBDD) is an ensemble of approaches used in the early stages of drug candidates identification which consists in the screening of small molecules, typically with a molecular weight below 250–300 Da and a logP value below 3
Since our comparison includes molecular dynamics (MD)-based strategies, we first investigated if the conditions used for the MD simulations and the force field chosen wereappropriate to simulate the correct behavior of water.To address this issue, we performed an MD simulation of the HSP90 in the apostate and subjected to AquaMMaps [6] toassess if the regions with predicted stationary water molecules were in agreement with the position of those having low B-factor observed in X-ray structures
AquaMMapsisa software that, through a posteriori analysis of water molecule trajectories during explicit solvent molecular dynamics simulations can calculate for each space region an occupancy value that expresses the ratio between the time during which a water molecule is located in that region during the dynamics and the total time of the simulation
Summary
Fragment-Based Drug Discovery [1] (FBDD) is an ensemble of approaches used in the early stages of drug candidates identification which consists in the screening of small molecules, typically with a molecular weight below 250–300 Da and a logP value below 3 (these empirical criteria are known as the “rule of three” [2]). Fragment screens lead to the identification of a subset of hit-fragments having an affinity range from μM to mM to the target. Their identification only represents the beginning of an iterative optimization process to turn a weak fragment into a mature high-affinity lead [3]. One of the challenging aspects of FBDD is the detection of such weak binders commonly achieved by high-sensitivity biophysical techniques, such as isothermal titration calorimetry (ITC), surface plasmon resonance (SPR), thermal shift assay, nuclear magnetic resonance (NMR), and X-ray crystallography (XRC), with only the last two methodologies able to provide structural information. The virtual screening of fragments is typically a challenging task; mostly due to the weak performance of scoring functions used to discriminate native from non-native poses [3,4]
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