In Silico Approaches to Prediction of Aqueous and DMSO Solubility of Drug-Like Compounds: Trends, Problems and Solutions

Abstract

The solubility of drugs and drug-like compounds has been the subject of extensive studies aimed at finding a way to predict solubility from molecular structure. The aqueous solubility of a drug is an important factor that influences its absorption, distribution and elimination in the body. Poor aqueous solubility often causes a drug to appear inactive and may cause other biological problems. Compound solubility in DMSO represents another serious problem in early stages of drug discovery. An appreciation of the factors affecting a compound's DMSO solubility could help in predicting the storage conditions and appropriateness of compounds for primary bioscreening programs. In silico procedures for estimation of water and DMSO solubility represent extremely useful tools for the drug discovery practitioners. In this review, we provide a critical discussion of in silico models for the prediction of DMSO and water solubility of drug-like compounds used for virtual screening. We describe the main tendencies in the field, "booming" approaches and unsolved problems. A critical analysis of the accuracy and applicability of methods is provided.

Suggested Improvements for Measurement of Equilibrium Solubility-pH of Ionizable Drugs

“…Focusing on the pH region where ͞ n H is expected to be near halfintegral, the CheqSol instrument quickly dissolves the solid by raising the pH for acids (e.g., to [10][11][12] or lowering the pH for bases (e.g., to 1-2). Afterwards, the original pH is re-established by adding acid/base titrant, whereupon the solid re-precipitates, possibly as an amorphous phase.…”

“…Since the mid-1990s there has been a heightened effort in drug discovery to predict drug-relevant aqueous solubility, described in at least a hundred publications (e.g., Huuskonen et al [1,2]; Abraham and Le [3]; Jorgensen and Duffy [4,5]; Bergström et al [6]; Hou et al [7]; Delaney [8]; Dearden [9]; Balakin et al [10]; Taskinen and Norinder [11]; Jain and Yalkowsky [12]; Shayanfar and Jouyban [13]; Wang and Hou [14]; Elder and Holm [15]; McDonagh et al [16]). The typical errors in drug solubility prediction are 0.7 -1.0 log unit, and for low-soluble compounds, errors are considerably greater than a log unit (Jorgensen and Duffy [5]; Palmer and Mitchell [17]).…”

ADMEProfiling in Drug Discovery and Development: An Overview

“…In silico models for solubility take into account log P , melting point, crystal packing, intrinsic solubility, and ionization effects [56][57][58][59][60]. From the simple general solubility equation, to more complex models based on Monte Carlo simulations using 2D or 3D properties, and fragmental or atom-based or quantum-chemical methods have all been used to predict aqueous as well as Dimethyl sulfoxide (DMSO) solubility of compounds with fair accuracy.…”

In Silico Classification of Solubility using Binary k‐Nearest Neighbor and Physicochemical Descriptors

“…The solubility of a drug candidate is important as solubility together with the dissolution rate, determines the fraction of the dose available for absorption. If the solubility or rate of dissolution is too low, the orally distributed drug will mostly be excreted without entering the blood and thus be inefficient [1]. Low solubility can also lead to unreliable results during in vitro testing and insoluble precipitates have been shown to cause false positives in bioassays, wasting valuable time and resources.…”