Use of Integrated Computational Approaches in the Search for New Therapeutic Agents

Abstract

Computer-aided drug discovery plays a strategic role in the development of new potential therapeutic agents. Nevertheless, the modeling of biological systems still represents a challenge for computational chemists and at present a single computational method able to face such challenge is not available. This prompted us, as computational medicinal chemists, to develop in-house methodologies by mixing various bioinformatics and computational tools. Importantly, thanks to multi-disciplinary collaborations, our computational studies were integrated and validated by experimental data in an iterative process. In this review, we describe some recent applications of such integrated approaches and how they were successfully applied in i) the search of new allosteric inhibitors of protein-protein interactions and ii) the development of new redox-active antimalarials from natural leads.

Cooperative Binding of the Cationic Porphyrin Tris-T4 Enhances Catalytic Activity of 20S Proteasome Unveiling a Complex Distribution of Functional States

“…§ In order to simulate the dynamics of the ligand-protein recognition event, we applied an original docking protocol based on a Monte Carlo-Metropolis search followed by a simulated annealing (SA) procedure [ 53 , 54 , 55 ]. Restraints were applied only to the backbone atoms of the calculated conserved secondary strucures ( Table S15 ) (see the Experimental Section for details).…”

Drug Treatments for Core Symptoms of Autism Spectrum Disorder: Unmet Needs and Future Directions

“…To date, strategies to improve drug development that aim at regulating the pathophysiological anomalies of a complex disorder have primarily been established through the study of single-gene disorders frequently associated with it. 30 This could be a promising approach because these single-gene disorders might be treated by developing specific pharmacological compounds based on cellular, molecular, and animal models of well-known genetic syndromes. Subsequently, the same compounds might target different syndromes with similar pathological mechanisms.…”

“…Subsequently, the same compounds might target different syndromes with similar pathological mechanisms. 30 Promising results in humans have already been communicated for some of these drugs initially aimed at treating the original single-gene disorders. 31 In this context, understanding the neurobiological alteration that a specific drug might target, is based on the study of new medications acting on known syndromic forms associated with autism, such as Joubert syndrome, Smith-Lemli-Opitz syndrome, tuberous sclerosis, or fragile X syndrome.…”

Identification of Potential Inhibitors of Cathepsin‐B using Shape & Pharmacophore‐based Virtual Screening, Molecular Docking and Explicit Water Thermodynamics

“…Ideal inhibitor of catB, therefore, should target only the endopeptidase activity while leaving physiological exopeptidase activity untouched. Computer aided drug design is an attractive strategy to cover the vast chemical space of binders at reduced cost and a more efficient approach than a brute force high‐throughput screens . On the computational side, high throughput docking or virtual screening is an asset when it comes to finding small molecule ligands of proteins .…”

“…Computer aided drug design is an attractive strategy to cover the vast chemical space of binders at reduced cost and a more efficient approach than a brute force high-throughput screens. [11][12][13][14] On the computational side, high throughput docking or virtual screening is an asset when it comes to finding small molecule ligands of proteins. [15][16][17] Considerable number of reports does suggest that virtual screening, docking and dynamics combined have been successfully employed for identification of inhibitors against many validated drug targets.…”