Carlton A. Taft

Current topics in computer‐aided drug design

The addition of computer-aided drug design (CADD) technologies to the research and drug discovery approaches could lead to a reduction of up to 50% in the cost of drug design. Designing a drug is the process of finding or creating a molecule which has a specific activity on a biological organism. Development and drug discovery is a time-consuming, expensive, and interdisciplinary process whereas scientific advancements during the past two decades have altered the way pharmaceutical research produces new bioactive molecules. Advances in computational techniques and hardware solutions have enabled in silico methods to speed up lead optimization and identification. We will review current topics in computer-aided molecular design underscoring some of the most recent approaches and interdisciplinary processes. We will discuss some of the most efficient pathways and design.

MOLECULAR DYNAMICS, DOCKING, DENSITY FUNCTIONAL, AND ADMET STUDIES OF HIV-1 REVERSE TRANSCRIPTASE INHIBITORS

Molecular dynamics, density functional with correlation, as well as docking studies of inhibitors of HIV-1 reverse transcriptase (RT) are reported. We propose in this work a novel potential HIV-1 RT inhibitor (RTI), which theoretically appears to bind in a similar mode as other nucleoside reverse transcriptase inhibitors, and in addition, it introduces a new hydrogen bond interaction with Trp229. Our novel RTI has high docking scores and the molecular dynamics studies, as well as the analysis of the ligand-receptor interactions in the active site and the ADMET properties suggest advantages and specificities for this potential RTI.

COMPUTER-AIDED MOLECULAR DESIGN OF NOVEL HMG-CoA REDUCTASE INHIBITORS FOR THE TREATMENT OF HYPERCHOLESTEROLEMIA

Elevated cholesterol levels are a primary risk factor for the development of coronary artery disease. Dietary changes associated with drug therapy can reduce high serum cholesterol levels and dramatically decrease the risk of stroke and overall mortality. HMG-CoA reductase is an important molecular target of hypolipemic drugs, known as statins, which are effective in the reduction of cholesterol serum levels, attenuating cholesterol synthesis in-liver by competitive inhibition regarding the substrate HMG-CoA. In this paper, we have focused on computer-aided molecular design using density functional theory, flexible docking, molecular dynamics as well as ADME, and synthetic accessibility analyses in order to propose novel potential HMG-CoA reductase inhibitors, designed by bioisosteric modifications which are promising for the treatment of hypercholesterolemia.

Ab initio and density functional study of the 5-pentacyclo[6.2.1.13.6.02.7.04,10]dodecyl cation. A symmetrical μ-hydride bridged carbocation

Abstract MP2/6-31g(d,p) and B3LYP/6-31g(d,p) calculations for the pentacyclo[6.2.1.1 3,6 .0 2,7 .0 4,10 ]dodecyl cation reveal two minima on the potential energy surface. The most stable minimum is the μ-hydride bridged cation 2 . The second minimum is the two-electron three-center bonded structure 3 . At MP2/6-31g(d,p) 2 is only 0.2 kcal/mol more stable than 3 , but at B3LYP/6-31g(d,p) this energy difference increases to 3.3 kcal/mol. The energy difference between 2 and 3 is only 3.8 kcal/mol. Solvent effect does not affect these numbers significantly. This low energy barrier may account for the product distribution observed on solvolysis of pentacyclic derivatives.