Recent Advances in Ligand-Based Drug Design: Relevance and Utility of the Conformationally Sampled Pharmacophore Approach

Abstract

In the absence of three-dimensional (3D) structures of potential drug targets, ligand-based drug design is one of the popular approaches for drug discovery and lead optimization. 3D structure-activity relationships (3D QSAR) and pharmacophore modeling are the most important and widely used tools in ligand-based drug design that can provide crucial insights into the nature of the interactions between drug target and ligand molecule and provide predictive models suitable for lead compound optimization. This review article will briefly discuss the features and potential application of recent advances in ligand-based drug design, with emphasis on a detailed description of a novel 3D QSAR method based on the conformationally sample pharmacophore (CSP) approach (denoted CSP-SAR). In addition, data from a published study are used to compare the CSP-SAR approach to the Catalyst method, emphasizing the utility of the CSP approach for ligand-based model development. Keywords: CoMFA, computer-aided drug design, CoMSIA, CSP, drug discovery, lead optimization, pharmacophore, Ligand-Based Drug Design, silico chemical alteration, conformationally-sampled pharmacophore (CSP), SAR method, molecular mechanics, quantum mechanical methods, Multivariable linear regression analysis (MLR), Principal component analysis (PCA), Partial least square analysis (PLS), MATLAB, Bayesian regularized artificial neural network (BRANN), internal validation, external validation, k-fold cross, Hansch/Free- Wilson method, CATALYST, Hydrogen-bond acceptor, Hydrogen-bond donor, Positively charges group (basic), Negatively charged group (acidic), Aromatic ring, Aliphatic hydrophobic moieties, Aromatic hydrophobic moieties, Apical Sodium-dependent Bile acid Transporter or ASBT, NG-OA distance, OA-NG-CG angles, molecular dynamics (MD), Monte Carlo (MC) simulations, CHARMM, AMBER, MMFF, quantum mechanical (QM), replica-exchange MD simulations, Generalized Born Continuum Solvent Model GBMV, Akaike information criteria, SHELL, AIC values, opioid ligands, nonpeptidic opioids, hASBT, DAT/SERT, Accelrys, San Diego, CA, RMSD